3-(anilinomethylene) oxindoles as protein tyrosine kinase and protein serine/threonine kinase inhibitors

ABSTRACT

Compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, A, D, X, Y and Z have the meaning as defined in the claims exhibit protein tyrosine kinase and protein serin/threonine kinase inhibitory activity.

This application is filed pursuant to 35 U.S.C. §371 as a U.S. NationalPhase Application of International Application No. PCT/US00/05057 filedFeb. 28, 2000 now WO 06/56710 Sep. 28, 2000, which claims priority from9904933.0 filed Mar. 4, 1999.

The present invention relates generally to novel amine substitutedoxindole compounds and compositions having utility as pharmacologicalagents in treating diseases or conditions alleviated by the inhibitionor antagonism of protein kinase activated signalling pathways ingeneral, and in particular in the pathological processes which involveaberrant cellular proliferation, such as tumor growth, restenosis,atherosclerosis, and thrombosis and methods for using and manufacturingsuch compounds. In particular, the present invention relates to a seriesof substituted oxindole compounds, which exhibit protein tyrosine kinaseand protein serine/threonine kinase inhibition, and which are useful ininhibiting tumor growth via inhibition of tumor-related angiogenesis.

BACKGROUND OF THE INVENTION

Protein kinases play a critical role in the control of cell growth anddifferentiation and are key mediators of cellular signals leading to theproduction of growth factors and cytokines. See, for example,Schlessinger and Ullrich, Neuron 1992, 9, 383. A partial non-limitinglist of such kinases includes abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf,Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms,c-fms, c-kit, c-met, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3,ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5,Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1,IKK2, IKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK,JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC,PKCα, PKCβ, PKCδ, PKCε, PKCγ, PKCλ, PKCμ, PKCζ, PLK1, Polo-like kinase,PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yesand Zap70. Protein kinases have been implicated as targets in centralnervous system disorders such as Alzheimer's (Mandelkow, E. M. et al.FEBS Lett. 1992, 314, 315. Sengupta, A. et al. Mol. Cell. Biochem. 1997,167,99), pain sensation (Yashpal, K. J. Neurosci. 1995, 15, 3263-72),inflammatory disorders such as arthritis (Badger, J. Pharm. Exp. Ther.1996, 279, 1453), psoriasis (Dvir, et al, J. Cell Biol. 1991, 113, 857),and chronic obstructive pulmononary disease, bone diseases such asosteoporosis (Tanaka et al, Nature, 1996, 383, 528), cancer (Hunter andPines, Cell 1994, 79, 573), atherosclerosis (Hajjar and Pomerantz, FASEBJ. 1992, 6, 2933), thrombosis (Salari, FEBS 1990, 263, 104), metabolicdisorders such as diabetes (Borthwick, A. C. et al. Biochem. Biophys.Res. Commun. 1995, 210, 738), blood vessel proliferative disorders suchas angiogenesis (Strawn et al Cancer Res. 1996, 56, 3540; Jackson et alJ. Pharm. Exp. Ther. 1998, 284, 687), restenosis (Buchdunger et al,Proc, Nat Acad. Sci USA 1991, 92, 2258), autoimmune diseases andtransplant rejection (Bolen and Brugge, Ann. Rev. Immunol. 1997, 15,371) and infectious diseases such as viral (Littler, E. Nature 1992,358, 160), and fungal infections (Lum, R. T. PCT Int. Appl., WO 9805335A1 980212).

The VEGF-R2 kinase is a receptor tyrosine kinase found in endothelialcells and is involved in angiogenesis—the growth and proliferation ofblood vessels from existing capillaries. Angiogenesis plays an importantrole in development, homeostasis, wound healing, the female reproductivecycle, and in pathological conditions such as rheumatoid arthritis,diabetic retinopathy, macular degeneration, psoriasis and cancer.VEGF-R2 kinase transmits the signal initiated by binding of VascularEndothelial Growth Factor (VEGF) to the extracellular receptor. Signaltransmission to the cell interior is accomplished via tyrosinephosphorylation by VEGF-R2, which prompts proliferation of endothelialcells and the release of cytokines and other cellular processes thatresult in the growth of new blood vessels. Angiogenesis is critical tothe growth of cancerous tumors. Solid tumors will not grow beyond 1-2 mmin size without the support of additional vascularization. Most tumortypes, if not all, secrete VEGF in order to stimulate angiogenesis.Inhibition of VEGF-R2 kinase would therefore interrupt a criticalprocess involved in tumor growth and metastasis as well as otherpathologic angiogenic conditions.

SUMMARY OF THE INVENTION

In brief summary, the invention comprises compounds of the formula (I):

wherein

Y, Z, A, and D are independently selected from the group consisting of:carbon and nitrogen, with the provisos that: (1) Z and D may benitrogen, but otherwise no more than one of Y, Z, A, and D may benitrogen, and (2) when Y, Z, or A are nitrogen, substituent R¹, R², orR³ designated for the respective nitrogen atom is non-existent;

X is selected from the group consisting of: N, CH, CCF₃, and C(C₁₋₁₂aliphatic);

R¹ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,thiol, hydroxy, hydroxy-C₁₋₁₂ aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic,R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂aliphatic, C₁₋₁₂ alkoxy, Aryloxy, amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl, C₁₋₁₂ alkoxycarbonyl, fluoro, bromo, iodo, cyano,sulfonamide, or nitro, where R⁹, Aryl, Cyc and Het are as defined below;

R² is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,N-hydroxyimino-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic,C₁₋₁₂ alkoxycarbonyl, carboxyl C₁₋₁₂ aliphatic, Aryl,R⁹-Aryl-oxycarbonyl, R⁹-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₁₂aliphatic-aminocarbonyl, Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,R⁹-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl, Het-C₁₋₁₂aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl, C₁₋₁₂ alkoxy-C₁₋₁₂aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphaticaminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen, hydroxy, C₁₋₁₂aliphatic-sulfonyl, aminosulfonyl, and C₁₋₁₂ aliphatic-aminosulfonyl,where R⁹, Aryl and Het are as defined below, with the proviso that whereX is nitrogen, R² is not chloro or3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl;

R¹ and R² are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by a substituent selected from the group consisting of:C₁₋₁₂ aliphatic, halogen, nitro, cyano, C₁₋₁₂ alkoxy, amino, hydroxyl,(R¹⁰,R¹¹)-amino, and oxo;

R³ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,hydroxy, hydroxy C₁₋₁₂ aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxy,Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen,where Aryl and Het are as defined below, with the proviso that where Xis nitrogen R³ is not fluoro;

R² and R³ are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₆ aliphatic or C₁₋₆ aliphatic-carbonyl;

with the proviso that R¹, R², and R³ cannot simultaneously be hydrogen;

R⁴, R⁵ and R⁶ may be the same or different and are independentlyselected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic, thiol,C₁₋₆aliphatic-thio, di(trifluoromethyl)hydroxymethyl, carboxamide,mono-C₁₋₁₂aliphatic aminocarbonyl, hydroxy, hydroxy-C₁₋₁₂ aliphatic,Aryl, Aryl-C₁₋₁₂ aliphatic, R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy, Het-oxy,amino, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic aminocarbonyl,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic alkoxycarbonyl, (R¹⁰,R¹¹)-amino-C₁₋₁₂aliphatic aminocarbonylamino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticalkoxycarbonylamino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticsulfonyl, Het-C₁₋₆aliphatic aminocarbonyl, Het-C₁₋₆ aliphatic aminocarbonylamino, Het-C₁₋₆alkoxycarbonylamino, Het-C₁₋₆ aliphatic carbonyl, Het-C₁₋₆alkoxycarbonyl, C₁₋₆ aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl, C₁₋₆aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl-Het-, C₁₋₆ alkoxycarbonyl,C₁₋₆ aliphatic carbonylamino, (C₁₋₆ aliphatic carbonyl)(C₁₋₆aliphatic)amino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonylamino,[(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonyl][C₁₋₆ aliphatic]amino,(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic sulfonylamino, [(R^(10,R) ¹¹)-amino-C₁₋₆aliphaticsulfonyl][C₁₋₆ aliphatic]amino, halogen, cyano,diethoxyphosphorylmethyl, nitro, trifluromethyl, and trifluoromethoxy,where R⁹, R¹⁰, R¹¹, Aryl, Cyc and Het are as defined below, with theproviso that where X is nitrogen, R⁴, R⁵ and R⁶ is not nitro;

R⁷ and R⁸ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, halogen, C₁₋₁₂ alkoxy, hydroxy,C₁₋₃-aliphatic, and C₁₋₃ aliphatic;

with the proviso that R⁴, R⁵, R⁶, R⁷, and R⁸ cannot simultaneously behydrogen;

wherein R⁷ may additionally be optionally fused to R⁵ so as to form afused benzo ring from the R⁵ to the R⁷ positions;

R⁹ is selected from the group consisting of: C₁₋₁₂ aliphatic, hydroxy,C₁₋₁₂ alkoxy and halogen;

R¹⁰ and R¹¹ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, C₁₋₆ aliphatic and Het;

Aryl is selected from the group consisting of: phenyl, naphthyl,phenanthryl and anthracenyl;

Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally hasone or more degrees of unsaturation;

Het is a saturated or unsaturated heteroatom ring system selected fromthe group consisting of: benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperidine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,quinoline, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole,thiatriazote, thiazine, thiazole, thiomorpholine, thiophene, thiopyran,triazine and triazole, where any of said heterocyclic rings may beoptionally substituted by a substituent selected from the groupconsisting of: C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, (R¹⁰,R¹¹)-amino,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic amino,oxo and dioxo;

and the pharmaceutically acceptable salts, polymorphs, esters, amides,carbamates, solvates, hydrates, affinity reagents and prodrugs thereofin either crystalline or amorphous form. The esters, amides andcarbamates, are preferably hydrolyzable and more preferably arebiohydrolyzable.

A more preferred genus of compounds of the present invention includescompounds of formula (II), defined as follows:

wherein

R¹ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,thiol, hydroxy, hydroxy-C₁₋₁₂ aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic,R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂aliphatic, C₁₋₁₂ alkoxy, Aryloxy, amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl, C₁₋₁₂ alkoxycarbonyl, fluoro, bromo, iodo, cyano,sulfonamide, or nitro, where R⁹, Aryl, Cyc and Het are as defined below;

R² is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,N-hydroxyimino-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic,C₁₋₁₂ alkoxycarbonyl, carboxyl C₁₋₁₂ aliphatic, Aryl,R⁹-Aryl-oxycarbonyl, R⁹-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₁₂aliphatic-aminocarbonyl, Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,R⁹-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl, Het-C₁₋₁₂aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl, C₁₋₁₂ alkoxy-C₁₋₁₂aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphaticaminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen, hydroxy, C₁₋₁₂aliphatic-sulfonyl, aminosulfonyl, or one or more substituents selectedfrom the group consisting of: C₁₋₁₂ aliphatic-aminosulfonyl, where R⁹,Aryl and Het are as defined below;

R¹ and R² are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₁₂ aliphatic, halogen, nitro, cyano, C₁₋₁₂ alkoxy,amino, hydroxyl, (R¹⁰, R¹¹)-amino, or oxo;

R³ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,hydroxy, hydroxy C₁₋₁₂ aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxy,Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen,where Aryl and Het are as defined below;

R² and R³ are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₆ aliphatic or C₁₋₆ aliphatic-carbonyl;

with the proviso that R¹, R² and R³ cannot simultaneously be hydrogen;

R⁴, R⁵ and R⁶ may be the same or different and are independentlyselected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic, thiol,C₁₋₆aliphatic-thio, di(trifluoromethyl)hydroxymethyl, carboxamide,mono-C₁₋₁₂aliphatic aminocarbonyl, hydroxy, hydroxy-C₁₋₁₂ aliphatic,Aryl, Aryl-C₁₋₁₂ aliphatic, R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy, Het-oxy,amino, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic aminocarbonyl,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic alkoxycarbonyl, (R¹⁰,R¹¹)-amino-C₁₋₁₂aliphatic aminocarbonylamino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticalkoxycarbonylamino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticsulfonyl, Het-C₁₋₆aliphatic aminocarbonyl, Het-C₁₋₆ aliphatic aminocarbonylamino, Het-C₁₋₆alkoxycarbonylamino, Het-C₁₋₆ aliphatic carbonyl, Het-C₁₋₆alkoxycarbonyl, C₁₋₆ aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl, C₁₋₆aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl-Het-, C₁₋₆ alkoxycarbonyl,C₁₋₆ aliphatic carbonylamino, (C₁₋₆ aliphatic carbonyl)(C₁₋₆aliphatic)amino, (R¹⁰,R¹¹)amino-C₁₋₆ aliphatic carbonylamino,[(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonyl][C₁₋₆ aliphatic]amino,(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic sulfonylamino, [(R¹⁰,R¹¹)-amino-C₁₋₆aliphaticsUlfonyl][C₁₋₆ aliphatic]amino, halogen, cyano,diethoxyphosphorylmethyl, nitro, trifluromethyl, or trifluoromethoxy,where R⁹, R¹⁰, R¹¹, Aryl, Cyc and Het are as defined below;

R⁷ and R⁸ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, halogen, C₁₋₁₂ alkoxy, hydroxy,C₁₋₃-aliphatic and C₁₋₃ aliphatic;

with the proviso that R⁴, R⁵, R⁶, R⁷ and R⁸ cannot simultaneously behydrogen;

wherein R⁷ may additionally be optionally fused to R⁵ so as to form afused benzo ring from the R⁵ to the R⁷ positions;

R⁹ is selected from the group consisting of: C₁₋₁₂ aliphatic, hydroxy,C₁₋₁₂ alkoxy, or halogen;

R¹⁰ and R¹¹ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, C₁₋₆ aliphatic and Het;

Aryl is selected from the group consisting of: phenyl, naphthyl,phenanthryl or anthracenyl;

Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally hasone or more degrees of unsaturation;

Het is a saturated or unsaturated heteroatom ring system selected fromthe group consisting of: benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperidine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,quinoline, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole,thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran,triazine and triazole, where any of said heterocyclic rings may beoptionally substituted by a substituent selected from the groupconsisting of: C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, (R¹⁰,R¹¹)-amino,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic amino,oxo or dioxo;

and the pharmaceutically acceptable salts, esters, amides, carbamates,solvates, hydrates, affinity reagents and prodrugs thereof in eithercrystalline or amorphous form. The esters, amides and carbamates, arepreferably hydrolyzable and more preferably are biohydrolyzable.

Another preferred genus of compounds of the present invention includescompounds of formula (III), defined as follows:

wherein

R¹ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,thiol, hydroxy, hydroxy-C₁₋₁₂ aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic,R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂aliphatic, C₁₋₁₂ alkoxy, Aryloxy, amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl, C₁₋₁₂ alkoxycarbonyl, fluoro, bromo, iodo, cyano,sulfonamide, or nitro, where R⁹,

Aryl, Cyc and Het are as defined below;

R² is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,N-hydroxyimino-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic,C₁₋₁₂ alkoxycarbonyl, carboxyl C₁₋₁₂ aliphatic, Aryl,R⁹-Aryl-oxycarbonyl, R⁹-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₁₂aliphatic-aminocarbonyl, Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,R⁹-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl, Het-C₁₋₁₂aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl, C₁₋₁₂ alkoxy-C₁₋₁₂aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphaticaminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen, hydroxy, C₁₋₁₂aliphatic-sulfonyl, aminosulfonyl, or one or more substituents selectedfrom the group consisting of: C₁₋₁₂ aliphatic-aminosulfonyl, where R⁹,Aryl and Het are as defined below, with the proviso that R² is notchloro or 3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl;

R¹ and R² are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₁₂ aliphatic, halogen, nitro, cyano, C₁₋₁₂ alkoxy,amino, hydroxyl, (R¹⁰, R¹¹)-amino, or oxo;

R³ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,hydroxy, hydroxy C₁₋₁₂ aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxy,Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen,where Aryl and Het are as defined below, with the proviso R³ is notfluoro;

R² and R³ are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₆ aliphatic or C₁₋₆ aliphatic-carbonyl;

with the proviso that R¹, R² and R³ cannot simultaneously be hydrogen;

R⁴, R⁵ and R⁶ may be the same or different and are independentlyselected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic, thiol,C₁₋₆aliphatic-thio, di(trifluoromethyl)hydroxymethyl, carboxamide,mono-C₁₋₁₂aliphatic aminocarbonyl, hydroxy, hydroxy-C₁₋₁₂ aliphatic,Aryl, Aryl-C₁₋₁₂ aliphatic, R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy, Het-oxy,amino, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic aminocarbonyl,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic alkoxycarbonyl, (R¹⁰,R¹¹)-amino-C₁₋₁₂aliphatic aminocarbonylamino, (R¹,R¹¹)-amino-C₁₋₆ aliphaticalkoxycarbonylamino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticsulfonyl, Het-C₁₋₆aliphatic aminocarbonyl, Het-C₁₋₆ aliphatic aminocarbonylamino, Het-C₁₋₆alkoxycarbonylamino, Het-C₁₋₆ aliphatic carbonyl, Het-C₁₋₆alkoxycarbonyl, C₁₋₆ aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl, C₁₋₆aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl-Het-, C-₁₋₆ alkoxycarbonyl,C₁₋₆ aliphatic carbonylamino, (C₁₋₆ aliphatic carbonyl)(C₁₋₆aliphatic)amino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonylamino,[(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonyl][C₁₋₆ aliphatic]amino,(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic sulfonylamino, [(R¹⁰,R¹¹)-amino-C₁₋₆aliphaticsulfonyl][C₁₋₆ aliphatic]amino, halogen, cyano,diethoxyphosphorylmethyl, nitro, trifluromethyl, or trifluoromethoxy,where R⁹, R¹⁰, R¹¹, Aryl, Cyc and Het are as defined below, with theproviso that R⁴, R⁵ and R⁶ is not nitro;

R⁷ and R⁸ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, halogen, C₁₋₁₂ alkoxy, hydroxy,C₁₋₃-aliphatic and C₁₋₃ aliphatic;

with the proviso that R⁴, R⁵, R⁶, R⁷ and R⁸ cannot simultaneously behydrogen;

R⁹ is selected from the group consisting of C₁₋₁₂ aliphatic, hydroxy,C₁₋₁₂ alkoxy, or halogen;

R¹⁰ and R¹¹ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, C₁₋₆ aliphatic and Het;

Aryl is selected from the group consisting of: phenyl, naphthyl,phenanthryl or anthracenyl;

Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which mayhave one or more degrees of unsaturation;

Het is a saturated or unsaturated heteroatom ring system selected fromthe group consisting of benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperidine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,quinoline, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole,thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran,triazine and triazole, where any of said heterocyclic rings may beoptionally substituted by a substituent selected from the groupconsisting of C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, (R^(10,R)¹¹)-amino, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic, (R¹⁰,R¹)-amino-C₁₋₁₂aliphatic amino, oxo or dioxo;

and the pharmaceutically acceptable salts, esters, amides, carbamates,solvates, hydrates, affinity reagents and prodrugs thereof in eithercrystalline or amorphous form. The esters, amides and carbamates, arepreferably hydrolyzable and more preferably are biohydrolyzable.

Another preferred genus of compounds of the present invention includescompounds of formula (IV), defined as follows:

wherein

Y, Z, A, and D are independently selected from the group consisting of:carbon and nitrogen, with the provisos that: (1) Z and D may benitrogen, but otherwise no more than one of Y, Z, A, and D may benitrogen, and (2) when Y, Z, or A are nitrogen, substituent R¹, R², orR³ designated for the respective nitrogen atom is non-existent;

R¹ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,thiol, hydroxy, hydroxy-C₁₋₁₂ aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic,R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂aliphatic, C₁₋₁₂ alkoxy, Aryloxy, amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl, C₁₋₁₂ alkoxycarbonyl, fluoro, bromo, iodo, cyano,sulfonamide, or nitro, where R⁹, Aryl, Cyc and Het are as defined below;

R² is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,N-hydroxyimino-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic,C₁₋₁₂ alkoxycarbonyl, carboxyl C₁₋₁₂ aliphatic, Aryl,R⁹-Aryl-oxycarbonyl, R⁹-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₁₂aliphatic-aminocarbonyl, Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,R⁹-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl, Het-C₁₋₁₂aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl, C₁₋₁₂ alkoxy-C₁₋₁₂aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphaticaminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen, hydroxy, C₁₋₁₂aliphatic-sulfonyl, aminosulfonyl, or one or more substituents selectedfrom the group consisting of: C₁₋₁₂ aliphatic-aminosulfonyl, where Re,Aryl and Het are as defined below;

R¹ and R² are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₁₂ aliphatic, halogen, nitro, cyano, C₁₋₁₂ alkoxy,amino, hydroxyl, (R¹⁰, R¹¹)-amino, or oxo;

R³ is selected from the group consisting of: hydrogen, C₁₋₁₂ aliphatic,hydroxy, hydroxy C₁₋₁₂ aliphatic, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxy,Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen,where Aryl and Het are as defined below;

R² and R³ are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by C₁₋₆ aliphatic or C₁₋₆ aliphatic-carbonyl;

with the proviso that R¹, R² and R³ cannot simultaneously be hydrogen;

R⁴, R⁵ and R⁶ may be the same or different and are independentlyselected from the group consisting of hydrogen, C₁₋₁₂ aliphatic, thiol,C₁₋₆aliphatic-thio, di(trifluoromethyl)hydroxymethyl, carboxamide,mono-C₁₋₁₂aliphatic aminocarbonyl, hydroxy, hydroxy-C₁₋₁₂ aliphatic,Aryl, Aryl-C₁₋₁₂ aliphatic, R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy, Het-oxy,amino, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic aminocarbonyl,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic alkoxycarbonyl, (R¹⁰,R¹¹)-amino-C₁₋₁₂aliphatic aminocarbonylamino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticalkoxycarbonylamino, (R¹⁰,R¹)-amino-C₁₋₆ aliphaticsulfonyl, Het-C₁₋₆aliphatic aminocarbonyl, Het-C₁₋₆ aliphatic aminocarbonylamino, Het-C₁₋₆alkoxycarbonylamino, Het-C₁₋₆ aliphatic carbonyl, Het-C₁₋₆alkoxycarbonyl, C₁₋₆ aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl, C₁₋₆aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl-Het-, C₁₋₆ alkoxycarbonyl,C₁₋₆ aliphatic carbonylamino, (C₁₋₆ aliphatic carbonyl)(C₁₋₆aliphatic)amino, (R¹⁰,R¹¹)amino-C₁₋₆ aliphatic carbonylamino,[(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonyl][C₁₋₆ aliphatic]amino,(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic sulfonylamino, [(R¹⁰,R¹¹)-amino-C₁₋₆aliphaticsulfonyl][C₁₋₆ aliphatic]amino, halogen, cyano,diethoxyphosphorylmethyl, nitro, trifluromethyl, or trifluoromethoxy,where R⁹, R¹⁰, R¹¹, Aryl, Cyc and Het are as defined below;

R⁷ and R⁸ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, halogen, C₁₋₁₂ alkoxy, hydroxy,C₁₋₃-aliphatic and C₁₋₃ aliphatic;

with the proviso that R⁴, R⁵, R⁶, R⁷ and R⁸ cannot simultaneously behydrogen;

wherein R⁷ may additionally be optionally fused to R⁵ so as to form afused benzo ring from the R⁵ to the R⁷ positions;

R⁹ is selected from the group consisting of: C₁₋₁₂ aliphatic, hydroxy,C₁₋₁₂ alkoxy, or halogen;

R¹⁰ and R¹¹ may be the same or different and are independently selectedfrom the group consisting of: hydrogen, C₁₋₆ aliphatic and Het;

Aryl is selected from the group consisting of: phenyl, naphthyl,phenanthryl or anthracenyl;

Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and optionally hasone or more degrees of unsaturation;

Het is a saturated or unsaturated heteroatom ring system selected fromthe group consisting of benzimidazole, dihydrothiophene, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxadiazine, piperazine, piperidine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,quinoline, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole,thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran,triazine and triazole, where any of said heterocyclic rings may beoptionally substituted by a substituent selected from the groupconsisting of: C₁₋₁₂ aliphatic, hydroxy, C-₁₋₁₂ alkoxy, (R¹⁰,R¹¹)-amino,(R¹⁰,R¹¹)amino-C₁₋₁₂ aliphatic, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic amino,oxo or dioxo;

and the pharmaceutically acceptable salts, esters, amides, carbamates,solvates, hydrates, affinity reagents and prodrugs thereof in eithercrystalline or amorphous form. The esters, amides and carbamates, arepreferably hydrolyzable and more preferably are biohydrolyzable.

While the ensuing discussion refers to the compound of formula (I), itwill be understood that the compounds of formula (I) includes thecompounds of formulas (II), (III) and (IV); accordingly, referenceshereafter to formula (I) should hereafter be understood to includes thecompounds of formulas (II), (III) and (IV) as well as the compounds offormula (I). Furthermore, references in the ensuing discussion to theformula (I) should also be understood as referring to the compounds ofExamples 163-212 of Table 5 below which, while not included within thegeneral formula (I), have been found by the inventors to have Kinaseinhibiting properties.

Due to the presence of an oxindole exocyclic double bond, also includedin the compounds of the invention are their respective pure E and Zgeometric isomers as well as mixtures of E and Z isomers. The inventionas described and claimed does not set any limiting ratios on prevalenceof Z to E isomers.

Likewise, it is understood that compounds of formula (I) as used hereinincludes all tautomeric forms other than the specific tautomerrepresented by the formula.

Certain of the compounds as described contain one or more chiral, orasymmetric, centers and are therefore be capable of existing as opticalisomers that are either dextrorotatory or levorotatory. Also included inthe compounds of the invention are the respective dextrorotatory orlevorotatory pure preparations, and mixtures thereof.

Certain compounds of formula (I) above are optionally provided instereoisomeric forms (e.g. they may contain one or more asymmetriccarbon atoms or may exhibit cis-trans isomerism). The individualstereoisomers (enantiomers and diastereoisomers) and mixtures of theseare included within the scope of the present invention. Likewise, it isunderstood that compounds of formula (I) are optionally provided invarious tautomeric forms within the scope of the present invention.

The present invention also provides compounds of formula (I) andpharmaceutically acceptable salts thereof (hereafter collectivelyreferred to as the “active compounds”) for use in medical therapy, andparticularly in the treatment of disorders mediated by a Kinase, such asVEGF-R2 tyrosine kinase, including, for example, as angiogenesisaccompanying malignant tumor growth.

A further aspect of the invention provides a method of treatment of ahuman or animal suffering from a disorder mediated by a protein kinase,said treatment comprising administering an effective amount of an activecompound of formula (I) to the human or animal patient.

In a related aspect the present invention comprises a method forinhibiting a kinase comprising bringing said kinase into contact with acompound of formula (I).

Another aspect of the present invention provides a method for using anactive compound of formula (I), in the preparation of a medicament forthe treatment of malignant tumors, or for the treatment of disordersinvolving abnormal angiogenesis, such as arthritis, diabeticretinopathy, macular degeneration and psoriasis. Alternatively,compounds of formula (I) can be used in the preparation of a medicamentfor the treatment of a disease mediated by a kinase selected from thegroup consisting of: abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk,CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms,c-kit, c-met, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK,ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, Fps,Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R,Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK,MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCα, PKCβ, PKCδ,PKCε, PKCγ, PKCλ, PKCμ, PKCζ, PLK1, Polo-like kinase, PYK2, tie1, tie2,TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70.

Additionally, compounds of formula (I) can be used in the preparation ofa medicament for the treatment of organ transplant rejection, tumorgrowth, chemotherapy-induced mucositis, radiation-induced mucositis,plantar-palmar syndrome, chemotherapy-induced alopecia,chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopeniaand hirsutism or of treating a disease state selected from the groupconsisting of: mucocitis, restenosis, atherosclerosis, rheumatoidarthritis, angiogenesis, hepatic cirrhosis, glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, chronic obstructive pulmonarydisease, thrombotic microangiopathy, aglomerulopathy, psoriasis,diabetes mellitus, inflammation, a neurodegenerative disease, maculardegeneration, actinic keratosis and hyperproliferative disorders.

Another aspect of the present invention provides the use of an activecompound of formula (I), in coadministration or alternatingadministration with previously known anti-tumor therapies for moreeffective treatment of such tumors.

Another aspect of the present invention provides the use of an activecompound of formula (I) in the preparation of a medicament for thetreatment of viral or eukaryotic infections.

Other aspects of the present invention related to the inhibition ofprotein kinases are discussed in more detail below.

Compounds synthesized as part of the present invention which arecurrently preferred are listed in Tables 1-3 below. Compounds areidentified by the numbers shown in the first column; variables below inthe rest of the columns are with reference to the generic structure (I).Corresponding IUPAC nomenclature are disclosed in Table 4. Since allsubstituents at each point of substitution are capable of independentsynthesis of each other, the tables are to be read as a matrix in whichany combination of substituents is within the scope of the disclosureand claims of the invention.

TABLE 1 (II)

Example R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ 1 H H Br 4-morpholino H H H H 2 H H Br4-pyridylmethyl H H H H 3 —NH—C═N— H CH₃ H H H H 4 —NH—N═N— H NO₂ CH₃ HH H 5 —NH—N═N— H NO₂ CF₃ H H H 6 —NH—N═N— H NO₂ Cl H H H 7 —NH—N═N— HNO₂ CH₃ CH₃ H H 8 —NH—N═N— H —C(OH)(CF₃)₂ H H H H 9 —NH—N═N— H —CH₂CH₂OHH H H H 10 —S—CH═N— H Sme H H H H 11 —S—CH═N— H H OMe OMe H H 12—S—CH═N— H OH H H H H 13 —CH═CH—CH═N— H H OMe H H H 14 —CH═CH—CH═N— H HCN OMe H H 15 —CH═CH—CH═N— H CH₃ H H H H 16 —CH═CH—CH═N— H OMe H H H H17 —NH—N═N— H H CN H H H 18 —NH—N═N— H CH₃ H H H H 19 —NH—N═N— H OMe H HH H 20 —S—CH═N— H 4-morpholino H H H H 21 —S—CH═N— H NHAc H H H H 22—S—CH═N— H —CH₂CH₂OH H H H H 23 —S—CH═N— H 4-pyridylmethyl H H H H 24—S—CH═N— H CONH₂ H H H H 25 H H Br 4-morpholino H H H H 26 H H Br CONH₂H H H H 27 H H Br NHAc H H H H 28 H H Br —CH₂CH₂OH H H H H 29—CH═CH—CH═N— H 4-morpholino H H H H 30 —CH═CH—CH═N— H 4-pyridylmethyl HH H H 31 —CH═CH—CH═N— H NHAc H H H H 32 —CH═CH—CH═N— H —CH₂CH₂OH H H H H33 —CH═CH—CH═N— H CONH₂ H H H H 34 —CH═CH—CH═N— H OH H H H H 35 H H2-furanyl 4-morpholino H H H H 36 H H 2-furanyl NHAc H H H H 37 H H2-furanyl —CH₂CH₂OH H H H H 38 H H —CH═CH₂ 4-morpholino H H H H 39 H H—CH═CH₂ 4-pyridylmethyl H H H H 40 H H —CH═CH₂ NHAc H H H H 41 H H—CH═CH₂ —CH₂CH₂OH H H H H 42 H H 2-furanyl 4-pyridylmethyl H H H H 43 HH 2-furanyl OH H H H H 44 H H 2-thienyl 4-morpholino H H H H 45 H H2-thienyl NHAc H H H H 46 H H Br H —CH₂OH H H H 47 H H Br5-methyl-3-pyrazolon-1-yl H H H H 48 —S—CH═N— H3-ethyl-piperidine-2,6-dion-3-yl H H H H 49 —S—CH═N— H OPh H H H H 50—S—CH═N— H OCH₂Ph H H H H 51 —S—CH═N— H 4-(methoxycarbonyl)phenoxy H H HH 52 —S—CH═N— H 3-(methoxycarbonyl)phenoxy H H H H 53 —S—CH═N— H H—CH₂OH H H H 54 —S—CH═N— H H CONH₂ H H H 55 —S—CH═N— H5-methyl-3-pyrazolon-1-yl H H H H 56 —S—CH═N— H CO₂Me H H H H 57—S—CH═N— H CN H H H H 58 —S—CH═N— H NMeAc H H H H 59 —CH═CH—CH═N— H OPhH H H H 60 —CH═CH—CH═N— H OCH₂Ph H H H H 61 —CH═CH—CH═N— H4-(methoxycarbonyl)phenoxy H H H H 62 —CH═CH—CH═N— H3-(methoxycarbonyl)phenoxy H H H H 63 —CH═CH—CH═N— H3-ethyl-piperidine-2,6-dion-3-yl H H H H 64 —CH═CH—CH═N— H benzoyl H H HH 65 —CH═CH—CH═N— H H —CH₂OH H H H 66 —CH═CH—CH═N— H5-methyl-3-pyrazolon-1-yl H H H H 67 —CH═CH—CH═N— H2-(4-hydroxyphenyl)ethenyl H H H H 68 —CH═CH—CH═N— H H CONH₂ H H H 69—CH═CH—CH═N— H CN H H H H 70 —CH═CH—CH═N— H CO₂Me H H H H 71 —S—CH═N— HSO₂CH₂CH₂NEt₂ H H H H 72 —CH═CH—CH═N— H SO₂CH₂CH₂NEt₂ H H H H 73 H H PhH CONH₂ H H H 74 H H Ph —CH₂PO(OEt)₂ H H H H 75 H H Ph H CN H H H 76 H HPh H H H —CH₂CH₂OH H 77 H H Ph H —CH₂OH H H H 78 H H Ph H H H OMe H 79 HH Ph 5-methyl-3-pyrazolon-1-yl H H H H 80 H H Ph I H H H H 81 H H2-furanyl H CONH₂ H H H 82 H H 2-furanyl —CH₂PO(OEt)₂ H H H H 83 H H2-furanyl H CN H H H 84 H H 2-furanyl H H H —CH₂CH₂OH H 85 H H 2-furanylH —CH₂OH H H H 86 H H 2-furanyl H H H OMe H 87 H H 2-furanyl5-methyl-3-pyrazolon-1-yl H H H H 88 H H 2-furanyl I H H H H

TABLE 2 (III)

Ex- ample R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ 89 —NH—N═N— H OMe H H H H 90 —NH—N═N—H 5-oxazolyl H H H H 91 —NH—N═N— H CH₃ H H H H 92 —NH—N═N— H 2-(2-pyri-H H H H dyl)ethenyl 93 —S—CH═N— H H OMe H H H 94 CH₃ OH CH₃ CH₃ H H H H95 —NH—N═N— H CF₃ H H H H 96 —S—CH═N— H H F H H H 97 —S—CH═N— H F H H HH 98 —S—CH═N— H Br H H H H

TABLE 3 (IV)

Example Y Z A D R¹ R² R³ R⁴ R⁵ R⁷ R⁶ R⁸  99 C C C N H Ph H W CONH₂ H H H100 C C C N H Ph H —CH₂PO(OEt)₂ H H H H 101 C C C N H Ph H H CN H H H102 C C C N H Ph H H H —CH₂CH₂OH H H 103 C C C N H Ph H H —CH₂OH H H H104 C C C N H Ph H H H OMe H H 105 C C C N H Ph H5-methyl-3-pyrazolon-1-yl H H H H 106 C C C N H Ph H I H H H H 107 C C CN H 2-furanyl H H CONH₂ H H H 108 C C C N H 2-furanyl H —CH₂PO(OEt)₂ H HH H 109 C C C N H 2-furanyl H H CN H H H 110 C C C N H 2-furanyl H H H—CH₂CH₂OH H H 111 C C C N H 2-furanyl H H —CH₂OH H H H 112 C C C N H2-furanyl H H H OMe H H 113 C C C N H 2-furanyl H5-methyl-3-pyrazolon-1-yl H H H H 114 C C C N H 2-furanyl H I H H H H115 C C C N H 3-thienyl H H CONH₂ H H H 116 C C C N H 3-thienyl H—CH₂PO(OEt)₂ H H H H 117 C C C N H 3-thienyl H H CN H H H 118 C C C N H3-thienyl H H H —CH₂CH₂OH H H 119 C C C N H 3-thienyl H H —CH₂OH H H H120 C C C N H 3-thienyl H H H OMe H H 121 C C C N H 3-thienyl H5-methyl-3-pyrazolon-1-yl H H H H 122 C C C N H 3-thienyl H I H H H H123 C C C N H Br H H CONH₂ H H H 124 C C C N H Br H —CH₂PO(OEt)₂ H H H H125 C C C N H Br H H CN H H H 126 C C C N H Br H H H —CH₂CH₂OH H H 127 CC C N H Br H H —CH₂OH H H H 128 C C C N H Br H H H OMe H H 129 C C C N HBr H 5-methyl-3-pyrazolon-1-yl H H H H 130 C C C N H Br H I H H H H 131C C C N H H Cl H CONH₂ H H H 132 C C C N H H Cl —CH₂PO(OEt)₂ H H H H 133C C C N H H Cl H CN H H H 134 C C C N H H Cl H H —CH₂CH₂OH H H 135 C C CN H H Cl H —CH₂OH H H H 136 C C C N H H Cl H H OMe H H 137 C C C N H HCl 5-methyl-3-pyrazolon-1-yl H H H H 138 C C C N H H Cl I H H H H 139 CC C N H CO₂Et H H CONH₂ H H H 140 C C C N H CO₂Et H —CH₂PO(OEt)₂ H H H H141 C C C N H CO₂Et H H CN H H H 142 C C C N H CO₂Et H H H —CH₂CH₂OH H H143 C C C N H CO₂Et H H —CH₂OH H H H 144 C C C N H CO₂Et H H H OMe H H145 C C C N H CO₂Et H 5-methyl-3-pyrazolon-1-yl H H H H 146 C C C N HCO₂Et H I H H H H 147 C C C N H H H H CONH₂ H H H 148 C C C N H H H—CH₂PO(OEt)₂ H H H H 149 C C C N H H H H CN H H H 150 C C C N H H H H H—CH₂CH₂OH H H 151 C C C N H H H H —CH₂OH H H H 152 C C C N H H H H H OMeH H 153 C C C N H H H 5-methyl-3-pyrazolon-1-yl H H H H 154 C C C N H HH I H H H H 155 N C C C — H H H CONH₂ H H H 156 N C C C — H H—CH₂PO(OEt)₂ H H H H 157 N C C C — H H H CN H H H 158 N C C C — H H H H—CH₂CH₂OH H H 159 N C C C — H H H —CH₂OH H H H 160 N C C C — H H H H OMeH H 161 N C C C — H H 5-methyl-3-pyrazolon-1-yl H H H H 162 N C C C — HH I H H H H 163 C C C N H Ph H OH —CH═CH—CH═CH— H H 164 C C C N H2-furanyl H OH —CH═CH—CH═CH— H H 165 C C C N H 3-thienyl H OH—CH═CH—CH═CH— H H 166 C C C N H Br H OH —CH═CH—CH═CH— H H 167 C C C N HH Cl OH —CH═CH—CH═CH— H H 168 C C C N H CO₂Et H OH —CH═CH—CH═CH— H H 169C C C N H H H OH —CH═CH—CH═CH— H H 170 N C C N — H H OH —CH═CH—CH═CH— HH 171 C C C C H H 2-furanyl OH —CH═OH—CH═CH— H H 172 C C C C H H PhenylOH —CH═CH—CH═CH— H H

Standard accepted nomenclature corresponding to the Examples set forthin this specification are set forth below. In some cases nomenclature isgiven for one or more possible isomers.

TABLE 4 Example 1 6-Bromo-3-{(Z and E)-[4-(4-morpholinyl)anilino]-methylidene}-1,3-dihydro-2H-indol-2-one. Example 2 6-Bromo-3-{(Z andE)-[4-(4-pyridinylmethyl)anilino]-methylidene}-1,3-dihydro-2H-indol-2-one; Example 3 8-[(Z andE)4-Toluidinomethylidene]-6,8-dihydroimidazo- [4,5-e]indol-7(3H)-one;Example 4 8-[(Z and E)-(3-Methyl-4-nitroanilino)methylidene]-3,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one; Example 5 8-{(Z andE)-[4-Nitro-3-(trifiuoromethyl)anilino][methylidene}-3,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one; Example 68-[(Z and E)-(3-Chloro-4-nitroanilino)methylidene]-1,6-dihydro[1,2,3]triazolo[4,e]indol-7-one; Example 7 8-[(Z andE)-(3,5-Dimethyl-4-nitroanilino)methylidene]-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one; Example 8 8-((Z andE)-{4-[2,2,2-Trifluor-1-hydroxy-1-(trifiuoromethyl)ethyl]anilino}methylidene)-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one; Example 9 8-{(Z andE)-[4-(2-Hydroxyethyl)anilino]-methylidene}-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one; Example 108-{(Z)-[4-(Methylsulfanyl)anilino]methylidene)-6H-[1,3]thiazolo[5,4-e]indol-7-one; Example 118-[(Z)-(3,5-Dimethoxyanilino)methylidene]-6H-[1,3]-thiazolo[5,4-e]indol-7-one; Example 128-[(Z)-(4-Hydroxyanilino)methylidene]-6H-[1,3]thiazolo-[5,4-e]indol-7-one; Example 131-[(Z)-(3-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo-[3,2-f]quinolin-2-one; Example 143-{[(Z)-(2-Oxo-2,3-hydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl)amino}benzonitrile; Example 151-[(Z)-4-Toluidinomethylidene]-1,3-dihydro-2H-pyrrolo-[3,2-f]-quinolin-2-one; Example 161-[(Z)-(4-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 17 3-({[(Z andE)-7-Oxo-6,7-dihydro[1,2,3]triazolo[4,5-e]indol-8(1H)-ylidene]methyl}amino)benzonitrile; Example 18 8-[(Z andE)-4-Toluidinomethylidene]-1,6-dihydro[1,2,3]-triazolo[4,5-e]indol-7-one; Example 19 8-[(Z andE)-(4-Methoxyanilino)methylidene]-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one; Example 208-{(Z)-[4-(4-Morpholinyl)anilino]methylidene)-6H-[1,3]-thiazolo[5,4-e]indol-7-one; Example 21N-(4-{[(Z)-(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]-indol-8-ylidene)methyl]amino}phenyl)acetamide; Example 228-{(Z)-[4-(2-Hydroxyethyl)anilino]methylidene)-6H-[1,3]-thiazolo[5,4-e]indol-7-one; Example 238-{(Z)-[4-(4-Pyridinylmethyl)anilino]methylidene}-6H-[1,3]thiazoio[5,4-e]indol-7-one; Example 244-{[(Z)-(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzamide; Example 25 6-Bromo-3-{(Z andE)-[4-(4-morpholinyl)anilino]- methylidene)-1,3-dihydro-2H-indol-2-one;Example 26 4-{[(Z and E)-(6-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzamide; Example 27 N-(4-{[(Z andE)-(6-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)acetamide; Example 28 6-Bromo-3-{(Z andE)-[4-(2-hydroxyethyl)anilino]- methylidene)-1,3-dihydro-2H-indol-2-one;Example 29 1-{(Z)-[4-(4-Morpholinyl)anilino]methylidene)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 301-{(Z)-[4-(4-Pyridinylmethyl)anilino]methylidene)-1,dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 31N-(4-{[(Z)-(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}phenyl)acetamide; Example 321-{(Z)-[4-(2-Hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 334-{[(Z)-(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzamide; Example 341-[(Z)-(4-Hydroxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 35 6-(2-Furyl)-3-{(Z andE)-[4-(4-morpholinyl)anilino]- methylidene}-1,3-dihydro-2H-indol-2-one;Example 36 N-[4-({(Z and E)-[6-(2-Furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)phenyl]acetamide; Example 37 6-(2-Furyl)-3-{(Zand E)-[4-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one; Example 38 3-{(Z andE)-[4-(4-Morpholinyl)anilino]methylidene)-6-vinyl-1,3-dihydro-2H-indol-2-one; Example 39 3-{(Z andE)-[4-(4-Pyridinylmethyl)anilino]methylidene}-6-vinyl-1,3-dihydro-2H-indol-2-one; Example 40 N-(4-{(Z andE)-[(2-Oxo-6-vinyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)acetamide; Example 41 3-{(Z andE)-[4-(2-Hydroxyethyl)anilino]methylidene)-6-vinyl-1,3-dihydro-2H-indol-2-one; Example 42 6-(2-Furyl)-3-{(Z andE)-[4-(4-pyridinylmethyl)anilino]-methylidene}-1,3-dihydro-2H-indol-2-one; Example 43 6-(2-Furyl)-3-[(Zand E)-(4-hydroxyanilino)methylidene]- 1,3-dihydro-2H-indol-2-one;Example 44 3-{(Z and E)-[4-(4-Morpholinyl)anilino]methylidene)-6-(2-thienyl)- 1,3-dihydro-2H-indol-2-one; Example 45 N-[4-({(Z andE)-[2-Oxo-(2-thienyl)-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)phenyl]acetamide; Example 46 6-Bromo-3-{(Z andE)-[3-(hydroxymethyl)anilino]- methylidene)-1,3-dihydro-2H-indol-2-one;Example 47 6-Bromo-{(Z and E)-[4-(methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene)-1,3-dihydro-2H-indol- 2-one; Example48 3-Ethyl-3-(4-{(Z and E )-[(7-oxo-6,7-dihydro-8H-[1,3]-thiazolo[5,4-e]indol-8-ylidene)methyl]amino}-phenyl)-2,6-piperidinedione; Example 49 8-[(Z)-(4-Phenoxyanilino)methylidene]-6H-[1,3]thiazolo- [5,4-e]indol-7-one; Example 508-{(Z)-[4-(Benzyloxy)anilino]methylidene}-6H-[1,3]-thiazolo[5,4-e]indol-7-one; Example 51 Methyl4-(4-{[((Z)-7-oxo-6,7-dihydro-8H-[1,3]thiazolo-[5,4-e]indol-8-ylidene)methyl]amino}phenoxy)benzoate; Example 52 Methyl3-(4-{(Z)-[(7-oxo-6,7-dihydro-8H-[1,3}thiazolo-[5,4-e]indol-8-ylidene)methyl]amino}phenoxy)benzoate; Example 538-{(Z)-[3-(Hydroxymethyl)anilino]methylidene)-6H-[1,3]-thiazolo[5,4-e]indol-7-one; Example 543-{(Z)-[(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzamide; Example 558-{(Z)-[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene)-6H-[1,3]thiazolo[5,4]indol-7-one; Example 56Methyl 4-{(Z)-[(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo-[5,4-e]indol-ylidene)methyl]amino}benzoate; Example 574-{(Z)-[(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzonitrile; Example 58N-Methyl-N-(4-{(Z)-[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo-[5,4-e]indol-8-ylidene)methyl]amino}phenyl)acetamide; Example 591-[(Z)-(4-Phenoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo-[3,2-f]quinolin-2-one; Example 601-{(Z)-[4-(Benzyloxy)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 61 Methyl4-(4-{(Z)-[(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]-quinolin-1-ylidene)methyl]amino}phenoxy)benzoate; Example 62 Methyl3-(4-{(Z)-[(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]-quinolin-1-ylidene)methyl]amino}phenoxy)benzoate; Example 633-Ethyl-3-(4-{(Z)-[(2-oxo-2,3-dihydro-1H-pyrrolo[3,2-f]-quinolin-1-ylidene)methyl]amino}phenyl)-2,6- piperidinedione; Example 641-[(Z)-(4-Benzoylanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-one; Example 651-{(Z[3-(Hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one; Example 661-{(Z[4-(Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-anilino]methylidene}-1H-pyrrolo[3,2-f]quinolin-2(3H)-one Example 671-((EH)-4-[(E)-2-(4-Hydroxyphenyl)ethenyl]anilino}-methylidene)1,3-dihydro-2H-pyrrolo[3,2-f]quinoiin-2-one; Example 683-{(Z)-[(2-Oxo-2,3-dihydro-1H-pyrroio(3,2-f]quinolin-1-ylidene)methyl]amino}benzamide; Example 694-{(Z)-[(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzonitrile; Example 70 Methyl4-{(Z[(2-oxo-2,3-diihydro-1H-pyrrolo[3,2-f]-quinolin-1-ylidene)methyl]amino}benzoate; Example 718-[(Z)-(4-{[2-(Diethylamino)ethyl]sulfonyl}anilino)-methylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one; Example 721-[(Z)-(4-{[2-(Diethylamino)ethyl]sulfonyl}anilino)-methylidene]-1H-pyrrolo[3,2-f]quinolin-2(3H)-one; Example 73 3-{[(Z andE)-(2-Oxo-6-phenyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzamide; Example 74 Diethyl 4-{[(Z andE)-(2-oxo-phenyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzylphosphonate; Example 75 3-{[(Z andE)-(2-Oxo-6-phenyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzonitrile; Example 76 3-{(Z andE)-[2-(2-Hydroxyethyl)anilino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one; Example 77 3-{(Z andE)-[3-(Hydroxymethyl)anilino]methylidene[-6-phenyl-1,3-dihydro-2H-indol-2-one; Example 78 3-[(Z andE)-(2-Methoxyanilino)methylidene]-6-phenyl-1,3- dihydro-2H-indol-2-one;Example 79 3-{(Z and E)-[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-6-phenyl-1H-indol-2-one; Example 80 3-[(Z andE)-(4-lodoanilino)methylidene]-6-phenyl-1H- indol-2-one; Example 813-({(Z and E)-[6-(2-Furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)benzamide; Example 82 Diethyl 4-({(Z andE)-[6-(2-furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)benzylphosphonate; Example 83 3-({(Z andE)-[6-(2-Furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)benzonitrile; Example 84 6-(2-Furyl)-3-{(Z andE)-[2-(2-hydroxyethyl)anilino]- methylidene}-1,3-dihydro-2H-indol-2-one;Example 85 6-(2-Furyl)-3-{(Z and E)-[3-(hydroxymethyl)anilino]-methylidene}-1,3-dihydro-2H-indol-2-one; Example 86 6-(2-Furyl)-3-[(Zand E)-(2-methoxyanilino)methylidene]- 1,3-dihydro-2H-indol-2-one;Example 87 6-(2-Furyl)-3-{(Z and E )-[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene)-1H-indol-2-one; Example 886-(2-Furyl)-3-[(Z and E)-(4-iodoanilino)methylidene]-1H- indol-2-one;Example 89 3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-[N-(4-methoxyphenyl)hydrazone]; Example 903,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-{N-[4-(1,3-oxazol-5-yl)phenyl]hydrazone}; Example 913,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-[N-(4-methylphenyl)hydrazone]; Example 923,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-(N-{4-[(E)-2-(2-pyridinyl)ethenyl]phenyl}hydrazone); Example 936H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(3-methoxyphenyl)hydrazone]; Example 945-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione3-[N-(4-methylphenyl)hydrazone]; Example 953,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-{N-[4-(trifiuoromethyl)phenyl]hydrazone}; Example 966H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(3- fluorophenyl)hydrazone];Example 97 6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(4-fluorophenyl)hydrazone]; Example 986H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(4- bromophenyl)hydrazone];Example 99 3-{[(2-Oxo-5-phenyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide; Example 100 Diethyl4-{[(2-oxo-5-phenyl-1,2-dihydro-3H-pyrrolo-[2,3-b]-pyridin-3-ylidene)methyl]amino}- benzylphosphonate; Example 1013-{[(2-Oxo-5-phenyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile; Example 1023-{[2-(2-Hydroxyethyl)anilino]methylidene}-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1033-{[3-(Hydroxymethyl)anilino]methylidene)-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1043-[(2-Methoxyanilino)methylidene]-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1053-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-anilino]methylidene}-5-phenyl-1H-pyrrolo[2,3-b]pyridin- 2-one; Example106 3-[(4-lodoanilino)methylidene]-phenyl-1H-pyrrolo[2,3-b]-pyridin-2-one; Example 1073-({[5-(2-Furyl)-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]-pyridin-3-ylidene]methyl}amino)benzamide; Example 108 Diethyl4-({[5-(2-furyl)-2-oxo-1,2-dihydro-3H-pyrrolo-[2,3-b]-pyridin-3-ylidene]methyl}amino)- benzylphosphonate; Example 1093-({[5-(2-Furyl{2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]-pyridin-3-ylidene]methyl}amino)benzonitrile: Example 1105-(2-Furyl{3[2-(2-hydroxyethyl)anilino]methylidene{-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1115-(2-Furyl)-3[3-(hydroxymethyl)anilino]methylidene{-1,3-dihydro-2H-pyrrolo(2,3-b]pyridin-2-one; Example 1125-(2-Furyl{3-((2-methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo(2,3-b]pyridin-2-one; Example 1135-(2-Furyl{3{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene-1H-pyrrolo[2,3-b]pyridin-2-one; Example 1145-(2-Furyl)-3-[(4-iodoanilino)methylidene]-1H-pyrrolo-[2,3-b]pyridin-2-one; Example 1153-({[2-Oxo-5-(3-thienyl)-1,2-dihydro-3H-pyrrolo[2,3-b]-pyridin-3-ylidene]methyl}amino)benzamide; Example 116 Diethyl4-({[2-oxo-5-(3-thienyl)-1,2-dihydro-3H-pyrrolo-[2,3-b]pyridin-3-ylidene]methyl}amino)benzylphosphonate; Example 1173-({[2-Oxo-5-(3-thienyl)-1,2-dihydro-3H-pyrrolo[2,3-b]-pyridin-3-ylidene]methyl}amino)benzonitrile; Example 1183-{[2-(2-Hydroxyethyl)anilino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1193-{[3-(Hydroxymethyl)anilino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1203-[(2-Methoxyanilino)methylidene]-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1213-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1223-[(4-lodoanilino)methylidene]-5-(3-thienyl)-1H-pyrrolo-[2,3-b]pyridin-2-one; Example 1233-{[(5-Bromo-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide; Example 124 Diethyl4-{[(5-Bromo-2-oxo-1,2-dihydro-3H-pyrrolo-[2,3-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate; Example 1253-{[(5-Bromo-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile; Example 1265-Bromo-3}[2-(2-hydroxyethyl)anilino]methylidene}-1,3--dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1275-Bromo-3[3-(hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1285-Bromo-3-[(2-methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1295-Bromo-3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]- pyridin-2-one;Example 130 5-Bromo-3-[(4-iodoanilino)methylidene]1 H-pyrrolo[2,3-b]-pyridin-2-one; Example 1313-{[(6-Chloro-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide; Example 132 Diethyl4-{[(6-chloro-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]-pyridin-3-ylidene)methyl]amino}benzylphosphonate; Example 1333-{[(6-Chloro-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile; Example 1346-Chloro-3-{[2-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1356-Chloro-3-{[3-(hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1366-Chloro-3-[(2-methoxyanilino)methylidene]1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1376-Chloro-3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]- pyridin-2-one;Example 138 6-Chloro-3-[(4-iodoanilino)methylidene]1H-pyrrolo[2,3-b]-pyridin-2-one; Example 139 Ethyl3[3-(aminocarbonyl)anilino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-carboxylate; Example 140 Ethyl3-({4-[(diethoxyphosphoryl)methyl]anilino- }methylidene{2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]- pyridine-5-carboxylate; Example 141 Ethyl3-[(3-cyanoanilino)methylidene]-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Example 142 Ethyl3-{[2-(2-hydroxyethyl)anilino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Example 143 Ethyl3-{[3-(hydroxymethyl)anilino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Example 144 Ethyl3-[(2-methoxyaniiino)methylidene]-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate; Example 145 Ethyl3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-2-oxo-1,2-dihydro-3H-pyrrolo-[2,3-b]pyridine-5-carboxylate; Example 144 Ethyl3-[(4-iodoanilino)methylidene]-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridine-5-carboxylate; Example 1473-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide; Example 148 Diethyl4-{[(2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate; Example 1493-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile; Example 1503[2-(2-Hydroxyethyl)anilino]methylidene-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1513-{[3-(Hydroxymethyl)anilino]methylidene}1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1523-[(2-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo-[2,3-b]pyridin-2-one; Example 1533-{[4-(Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene-1H-pyrrolo[2,3-b]pyridin-2-one; Example 1543-[(4-lodoanilino)methylidene]-1H-pyrrolo[2,3-b]pyridin- 2-one; Example155 3[(2-Oxo-1,2-dihydro-3H-pyrrolo[3,2-b]pyridin-3-ylidene)methyl]amino}benzamide; Example 156 Diethyl4-{[(2-oxo-1,2-dihydro-3H-pyrrolo[3,2-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate; Example 1573-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[3,2-b]pyridin-3-ylidene)methyl]amino}benzonitrile; Example 1583-{[2-(2-Hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one; Example 1593-{[3-(Hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one; Example 1603-[(2-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one; Example 1613-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1H-pyrrolo[3,2-b]pyridin-2-one; and Example 1623-[(4-lodoanilino)methylidene]1H-pyrrolo[3,2-b]pyridin- 2-one. Example163 3-{(Z and E)-[(Hydroxy-1-naphthyl)amino]methylidene)-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1645-(2-Furyl)-3-{(Z and E )-[(4-hydroxy-1-naphthyl)amino]-methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1653-{(Z and E)-[(4-Hydroxy-1-naphthyl)amino]methylidene)-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1665-Bromo-3-{(Z and E)-[(4-hydroxy-1-naphthyl)amino]-methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 1676-Chloro-3-{(Z and E)-[(4-hydroxy-1-naphthyl)amino]-methylidene)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 168Ethyl 3-{(Z and E)-[(4-hydroxy-1-naphthyl)amino]-methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin- 5-carboxylate;Example 169 3-{(Z and E)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; Example 170 3-{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one; Example 171 6-(2-Furyl)-3-{(Zand E)-[(4-hydroxy-1-naphthyl)amino]-methylidene)-1,3-dihydr2H-indol-2-one; Example 172 3-{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one;

The invention discloses thirteen different points of substitution onstructural formula (I). Each of these points of substitution bears asubstituent whose selection and synthesis as part of this invention isindependent of all other points of substitution on formula (I). Eachpoint of substitution is now further described.

Preferred substitutions for Y, Z, A and D are nitrogen or carbon. Themost preferred substituents for D are nitrogen and carbon. The mosthighly preferred substituent for Y, Z, A and D is carbon.

Preferred substitutions at the R¹ position include hydrogen, fluoro,bromo, iodo, lower alkyl, cyano and nitro. Alternatively, R¹ isoptionally joined with R² to form a fused ring structure selected fromthe group consisting of: thiazole, imidazole, triazole and pyridine.Further, such fused ring structures are optionally substituted by one ormore substituents selected from the group consisting of: halogen, amino,lower alkyl substituted amino, lower alkyl and lower alkyl carbonyl. Ina preferred embodiment, R¹ is selected from the group which includeshydrogen and methyl or R¹ is fused with R² to form a ring structureselected from the group which includes fused thiazole and fusedpyridine. In a most highly preferred embodiment, R¹ is fused with R² toform a ring structure selected from the group which includes fusedthiazole, pyridine and pyridine substituted by halogen or methyl.

Preferred substitutions at the R² position include hydrogen, loweralkyl, lower alkoxy, hydroxy lower alkyl, C₁₋₁₂ alkoxycarbonyl, Aryl,Het, aminocarbonyl, lower alkyl aminocarbonyl, halogen and hydroxy.Alternatively, R² is fused with R¹ to form a fused ring selected fromthe group which includes thiazole, imidazole, triazole and pyridine.Such fused rings are optionally substituted by a substituent selectedfrom the group which includes halogen, amino, lower alkyl substitutedamino, lower alkyl and lower alkyl carbonyl. Most preferably, R² isselected from the group which includes hydroxyl, hydroxy and loweralkyl, or is fused with R¹ to form a ring structure selected from thegroup which includes fused thiazole and fused pyridine. In a most highlypreferred embodiment, R² is selected from the group which includeshydroxy and hydroxymethyl, or is fused with R¹ to form a fused ring fromthe group which includes fused thiazole, pyridine and pyridinesubstituted by halogen or methyl.

Preferred substitutions at R³ include hydrogen, lower alkyl, loweralkenyl, halogen, phenyl, Het and alkoxy. Most preferred are hydrogen,halogen, ethenyl and methyl. Most highly preferred substitutions at R³are hydrogen and bromo.

Preferred substitutions at R⁴ include hydrogen, lower alkyl, hydroxy,hydroxy-lower alkyl, carboxamide, mono-lower alkyl aminocarbonyl,substituted Aryl-lower alkyl, Het, Het-lower alkyl, lower alkoxy,Aryloxy, Het-oxy, amino, mono- or di-lower alkyl-amino lower alkylaminocarbonyl, mono- or di-lower alkyl-amino lower alkoxycarbonyl, mono-or di-lower alkyl-amino lower alkyl aminocarbonylamino, mono- ordi-lower alkyl-amino lower alkoxycarbonylamino, lower alkylcarbonylamino, (lower alkyl carbonyl)(lower alkyl)amino, mono- ordi-lower alkyl-amino lower alkyl carbonylamino, [mono- or di-loweralkyl-amino lower alkyl carbonyl][lower alkyl]amino, mono- or di-loweralkyl-amino lower alkyl sulfonylamino, [mono- or di-lower alkyl-aminolower alkyl sulfonyl][lower alkyl]amino, mono- or di-lower alkyl-aminolower alkyl sulfonyl, Het lower alkyl aminocarbonyl, Het lower alkylaminocarbonylamino, Het lower alkoxycarbonylamino, Het lower alkylcarbonyl, Het lower alkoxycarbonyl, lower alkyl sulfonyl lower alkylaminoalkyl, lower alkyl sulfonyl-lower alkyl-aminoalkyl-Het-, loweralkoxycarbonyl, halogen, cyano, diethoxyphosphorylmethyl, trifluromethyland trifluoromethoxy. The most preferred substitutions are lower alkyl,hydroxy, hydroxy-lower alkyl, carboxamide, mono-lower alkylaminocarbonyl, substituted Aryl-lower alkyl, Het, Het-lower alkyl,Het-oxy, mono- or di-lower alkyl-amino lower alkyl aminocarbonyl, mono-or di-lower alkyl-amino lower alkoxycarbonyl, mono- or di-loweralkyl-amino lower alkyl aminocarbonylamino, mono- or di-loweralkyl-amino lower alkoxycarbonylamino, lower alkyl carbonylamino, (loweralkyl carbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino loweralkyl carbonylamino, [mono- or di-lower alkyl-amino lower alkylcarbonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower alkylsulfonylamino, [mono- or di-lower alkyl-amino lower alkylsulfonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower alkylsulfonyl, Het lower alkyl aminocarbonyl, Het lower alkyl carbonyl, loweralkyl sulfonyl lower alkyl aminoalkyl, lower alkyl sulfonyl-loweralkyl-aminoalkyl-Het-, halogen, cyano and trifluromethyl. Most highlypreferred are hydroxymethyl, hydroxyethyl, 4-pyridylmethyl,4-morpholino, acetamido, N-methylacetamido, carboxamide,diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and3-ethyl-piperidine-2,6-dion-3-yl.

Preferred substitutions at R⁵ include hydrogen, lower alkyl, hydroxy,hydroxy-lower alkyl, carboxamide, mono-lower alkyl aminocarbonyl,substituted Aryl-lower alkyl, Het, Het-lower alkyl, lower alkoxy,Aryloxy, Het-oxy, amino, mono- or di-lower alkyl-amino lower alkylaminocarbonyl, mono- or di-lower alkyl-amino lower alkoxycarbonyl, mono-or di-lower alkyl-amino lower alkyl aminocarbonylamino, mono- ordi-lower alkyl-amino lower alkoxycarbonylamino, lower alkylcarbonylamino, (lower alkyl carbonyl)(lower alkyl)amino, mono- ordi-lower alkyl-amino lower alkyl carbonylamino, [mono- or di-loweralkyl-amino lower alkyl carbonyl][lower alkyl]amino, mono- or di-loweralkyl-amino lower alkyl sulfonylamino, [mono- or di-lower alkyl-aminolower alkyl sulfonyl][lower alkyl]amino, mono- or di-lower alkyl-aminolower alkyl sulfonyl, Het lower alkyl aminocarbonyl, Het lower alkylaminocarbonylamino, Het lower alkoxycarbonylamino, Het lower alkylcarbonyl, Het lower alkoxycarbonyl, lower alkyl sulfonyl lower alkylaminoalkyl, lower alkyl sulfonyl-lower alkyl-aminoalkyl-Het-, loweralkoxycarbonyl, halogen, cyano, diethoxyphosphorylmethyl, trifluromethyland trifluoromethoxy. The most preferred substitutions are lower alkyl,hydroxy, hydroxy-lower alkyl, carboxamide, mono-lower alkylaminocarbonyl, substituted Aryl-lower alkyl, Het, Het-lower alkyl,Het-oxy, mono- or di-lower alkyl-amino lower alkyl aminocarbonyl, mono-or di-lower alkyl-amino lower alkoxycarbonyl, mono- or di-loweralkyl-amino lower alkyl aminocarbonylamino, mono- or di-loweralkyl-amino lower alkoxycarbonylamino, lower alkyl carbonylamino, (loweralkyl carbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino loweralkyl carbonylamino, [mono- or di-lower alkyl-amino lower alkylcarbonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower alkylsulfonylamino, [mono- or di-lower alkyl-amino lower alkylsulfonyl][lower alkyl]amino, mono- or di-lower alkyl-amino lower alkylsulfonyl, Het lower alkyl aminocarbonyl, Het lower alkyl carbonyl, loweralkyl sulfonyl lower alkyl aminoalkyl, lower alkyl sulfonyl-loweralkyl-aminoalkyl-Het-, halogen, cyano and trifluromethyl. Most highlypreferred are hydroxymethyl, hydroxyethyl, 4-pyridylmethyl,4-morpholino, acetamido, N-methylacetamido, carboxamide,diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and3-ethyl-piperidine-2,6-dion-3-yl.

The most preferred substitution at R⁶ is hydrogen.

Preferred substitutions at R⁷ and R⁸ are hydrogen, halogen and methyl.

Another preferred substitution at R⁷ includes the state in which R⁷ isjoined to R⁵ so as to form a fused benzo ring from R⁵ to R⁷.

Preferred substitutions at X include N, CH and CCH₃. Most preferred isCH.

Preferred individual compounds of the present invention are selectedfrom the group consisting of:

Highly preferred compounds include

DETAILED DESCRIPTION OF THE INVENTION

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid or by reacting the acid with a suitable organic orinorganic base. Representative salts include the following salts:Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,Clavulanate, Citrate, Diethanolamine, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Metaphosphoric, Methylbromide, Methylnitrate, Methylsulfate,Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine,Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Trifluoroacetate, Triethiodide, Trimethylammonium and Valerate.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of formula (I) and these form a furtheraspect of the invention.

Also included within the scope of the invention are the individualisomers of the compounds represented by formula (I) above as well as anywholly or partially equilibrated mixtures thereof. The present inventionalso covers the individual isomers of the compounds represented byformula above as mixtures with isomers thereof in which one or morechiral asymmetric centers are inverted.

As used herein, the term “aliphatic” refers to the terms alkyl,alkylene, alkenyl, alkenylene, alkynyl and alkynylene.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group which includeslower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by a substituent selectedfrom the group inluding alkyl, nitro, cyano, halogen and lowerperfluoroalkyl, multiple degrees of substitution being allowed. Examplesof “alkyl” as used herein include, but are not limited to, n-butyl,n-pentyl, isobutyl, isopropyl and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

As used herein, the term “alkenylene” refers to an straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon - carbon double bonds, optionally substitutedwith substituents selected from the group which includes lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halogen and lowerperfluoroalkyl, multiple degrees of substitution being allowed. Examplesof “alkenylene” as used herein include, but are not limited to,ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon triple bonds, optionally substituted withsubstituents selected from the group which includes lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen and lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkynylene”as used herein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, the term “cycloaliphatic” includes the terms cycloalkyl,cycloalkylene, cycloalkenyl, cycloalkenylene, cycloalkynyl andcycloalkylnylene.

As used herein, “cycloalkyl” refers to a alicyclic hydrocarbon groupwith one or more degrees of unsaturation, having from three to twelvecarton atoms, optionally substituted with substituents selected from thegroup which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. “Cycloalkyl” includes by way of Examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like.

As used herein, the term “cycloalkylene” refers to a non-aromaticalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms, optionally substituted with substituents selected from thegroup which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “cycloalkenyl” refers to a substitutedalicyclic hydrocarbon radical having from three to twelve carbon atomsand at least one carbon-carbon double bond in the ring system,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 1-cyclopentene-3-yl,1-cyclohexene-3-yl, 1-cycloheptene-4-yl, and the like.

As used herein, the term “cycloalkenylene” refers to a substitutedalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms and at least one carbon-carbon double bond in the ringsystem, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 4,5-cyclopentene-1,3-diyl,3,4-cyclohexene-1,1-diyl, and the like.

As used herein, the term “heteroatom ring system” refers to the termsheterocyclic, heterocyclyl, heteroaryl and heteroarylene. Non-limitingexamples of such heteroatom ring systems are recited in the Summary ofthe Invention, above.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic ring having one ormore degrees of unsaturation containing one or more heteroatomicsubstitutions selected from S, SO, SO₂, O, or N, optionally substitutedwith substituents selected from the group which includes lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halogen, or lowerperfluoroalkyl, multiple degrees of substitution being allowed. Such aring may be optionally fused to one or more of another “heterocyclic”ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” include, butare not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane,piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical having one or more degreesof unsaturation containing one or more heteroatoms selected from S, SO,SO₂, O, or N, optionally substituted with substituents selected from thegroup which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more benzene rings or to one or more of another “heterocyclic” ringsor cycloalkyl rings. Examples of “heterocyclylene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, and the like.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings to form ring systems such asanthracene, phenanthrene and napthalene, optionally substituted withsubstituents selected from the group which includes lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl and aryl, multiple degrees of substitutionbeing allowed. Examples of aryl include, but are not limited to, phenyl,2-naphthyl, 1-naphthyl, biphenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group which includes lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl and aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited to,benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic heterocyclic aromaticring, containing one or more nitrogen, oxygen, or sulfur heteroatoms atany position, where N-oxides and sulfur monoxides and sulfur dioxidesare permissible heteroaromatic substitutions, optionally substitutedwith substituents selected from the group which includes lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano,halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systems, one ormore of the rings may contain one or more heteroatoms. Examples of“heteroaryl” used herein are furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole andindazole, and the like.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting of:lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. For polycyclicaromatic ring system diradicals, one or more of the rings may containone or more heteroatoms. Examples of “heteroarylene” used herein arefuran-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5diyl,pyridine-2,4-diyl, pyridine-2,3diyl, pyridine-2,5-diyl,pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is aliphatic.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is aliphatic.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is aliphatic.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is aliphatic.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is aliphatic, cycloaliphatic, or heterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is aliphatic.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aliphatic, cycloaliphatic, or heterocyclyl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” is inclusive of circumstances inwhich described condition is present and circumstances in which thedescribed condition is not present, for example, where the term is usedwith reference to a chemical substituent, it indicates the inclusion ofembodiments in which the specified substituent is present as well asembodiments in which the specified substituent is not present.

As used herein, the term “substituted” indicates the presence of thenamed substituent or substituents, and includes multiple degrees ofsubstitution.

As used herein, the terms “contain” or “containing” with reference toalkyl, alkenyl, alkynyl or cycloalkyl substituents indicates in-linesubstitution(s) with one or more substituents at any position along thealkyl, alkenyl, alkynyl or cycloalkyl substituents, such as one or moreof any of O, S, SO, SO₂, N, or N-alkyl, including, for example,—CH₂—O—CH₂—, —CH₂—SO₂—CH₂—, —CH₂—NH—CH₃ and so forth.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

The compounds of the present invention have the ability to crystallizein more than one form, a characteristic which is known as polymorphism,and such polymorphic forms (“polymorphs”) are within the scope of thepresent invention. Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

As used herein, the terms “biohydrolyzable carbonate”, “biohydrolyzableureide” and “biohydrolyzable carbamate” include carbonates, ureides, andcarbamates, respectively, of a compound of the general formula (I) whichcarbonates, ureides, and carbamates, do not completely diminish thebiological activity of the parent substance. Such carbonates, ureides,and carbamates may confer on the parent compound of the general formula(I) advantageous properties in vivo, such as improved duration ofaction, onset of action, and the like. Also included are compounds whichare relatively biologically inactive but which are converted in vivo bythe subject to the biologically active principle. An advantage of suchbiohydrolyzable forms is that, for example, they facilitate improvedoral administration because the carbonates, ureides, and carbamates aremore readily absorbed from the gut and are then transformed to acompound of formula (I) in plasma. Many examples of such biohydrolyzablecompounds are known in the art and include, by way of example, loweralkyl carbamates.

As used herein, the term “biohydrolyzable ester” is an ester of acompound of general formula which does not completely diminish thebiological activity of the parent substance. Such esters may confer onthe parent compound of the general formula (I) advantageous propertiesin vivo, such as improved duration of action, onset of action, and thelike. Also included are esters which are relatively biologicallyinactive but which are converted in vivo by the subject to thebiologically active principle. An advantage of such biohydrolyzableforms is that, for example, they facilitate improved oral administrationbecause they are more readily absorbed from the gut and are thentransformed to a compound of formula (I) in plasma. Many examples ofsuch biohydrolyzable esters are known in the art and include, by way ofexample, lower alkyl esters, lower acyloxy-alkyl esters, loweralkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkylesters and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of acompound of general formula which does not completely diminish thebiological activity of the parent substance. Such amides may confer onthe parent compound of the general formula (I) advantageous propertiesin vivo, such as improved duration of action, onset of action, and thelike. Also included are amides which are relatively biologicallyinactive but which are converted in vivo by the subject to thebiologically active principle. An advantage of such biohydrolyzableforms is that, for example, they facilitate improved oral administrationbecause they are more readily absorbed from the gut and are thentransformed to a compound of formula (I) in plasma. Many examples ofsuch biohydrolyzable are known in the art and include, by way ofexample, lower alkyl amides, α-amino acid amides, alkoxyacyl amides andalkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes compounds which arehydrolyzable in vivo to yield an active compound of formula (I),including for example, biohydrolyzable amides, biohydrolyzable estersand biohydrolyzable carbamates. The term “prodrug” also includescompounds in which the biohydrolyzable functionality is encompassed inthe compound of formula (I): for example, a lactam formed by acarboxylic group in R₁ and an amine in R₂, and compounds which may beoxidized or reduced biologically at a given functional group to yielddrug substances of formula (I). Examples of such functional groups are,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

As used herein, the term “affinity reagent” means a group attached tothe compound of formula (I) which does not affect its in vitrobiological activity, allowing the compound to bind to a target, yet sucha group binds strongly to a third component allowing a) characterizationof the target as to localization within a cell or other organismcomponent, perhaps by visualization by fluorescence or radiography, orb) facile separation of the target from an unknown mixture of targets,whether proteinaceous or not proteinaceous. An Example of an affinityreagent according to b) would be biotin either directly attached to (I)or linked with a spacer of one to 50 atoms selected from the groupconsisting of: C, H, O, N, S, or P in any combination. An Example of anaffinity reagent according to a) above would be fluorescein, eitherdirectly attached to (I) or linked with a spacer of one to 50 atomsselected from the group consisting of: C, H, O, N, S, or P in anycombination.

The term “effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher or clinician. The term “therapeutically effective amount”means any amount which, as compared to a corresponding subject who hasnot received such amount, results in improved treatment, healing,prevention, or amelioration of a disease or disorder, or a decrease inthe rate of advancement of a disease or disorder, and also includesamounts effective to enhance normal physiological function.

Whenever the terms “aliphatic” or “aryl” or either of their prefixesappear in a name of a substituent (e.g. arylalkoxyaryloxy) they includethose characteristics given above for “aliphatic” and “aryl”. Aliphaticor cycloalkyl substituents are term equivalents to those having one ormore degrees of unsaturation. Designated numbers of carbon atoms (e.g.C₁₋₁₀) refer independently to the number of carbon atoms in an aliphaticor cyclic aliphatic moiety or to the aliphatic portion of a largersubstituent in which the term “aliphatic” appears as a prefix (e.g.“al-”).

As used herein, the term “disubstituted amine” or “disubstituted amino-”includes either one or two substitutions on that particular nitrogenatom.

As used herein, the term “oxo” refers to the substituent=O.

As used herein, the term “halogen” or “halo” shall include iodine,bromine, chlorine and fluorine.

As used herein, the term “mercapto” refers to the substituent —SH.

As used herein, the term “carboxy” refers to the substituent —COOH.

As used herein, the term “cyano” refers to the substituent —CN.

As used herein, the term “aminosulfonyl” refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” refers to the substituent —C(O)NH₂.

As used herein, the term “sulfanyl” refers to the substituent —S—.

As used herein, the term “sulfenyl” refers to the substituent —S(O)—.

As used herein, the term “sulfonyl” refers to the substituent —S(O)₂—.

The compounds of formula (I) can be prepared readily according to thefollowing reaction General Synthesis Schemes (in which all variables areas defined before) and Examples or modifications thereof using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants which are themselves known to those of ordinary skill in thisart, but are not mentioned in greater detail.

The most preferred compounds of the invention are any or all of thosespecifically set forth in these examples. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise.

Abbreviations used in the Examples are as follows:

Abbreviations used in the Examples are as follows: g = grams mg =milligrams L = liters mL = milliliters M = molar N = normal mM =millimolar i.v. = intravenous p.o. = peroral s.c. = subcutaneous Hz =hertz mol = moles mmol = millimoles mbar = millibar psi = pounds persquare inch rt = room temperature min = minutes h = hours mp = meltingpoint TLC = thin layer chromatography R_(f) = relative TLC mobility MS =mass spectrometry NMR = nuclear magnetic resonance spectroscopy APCI =atmospheric pressure chemical ionization ESI = electrospray ionizationm/z = mass to charge ratio t_(r) = retention time Pd/C = palladium onactivated carbon ether = diethyl ether MeOH = methanol EtOAc = ethylacetate TEA = triethylamine DIEA = diisopropylethylamine THF =tetrahydrofuran DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide DDQ= 2,3-dichloro-5,6-dicyano-1,4-benzoquinone LAH = lithium aluminumhydride TFA = trifluoroacetic acid LDA = iithium diisopropylamide THP =tetrahydropyranyl NMM = N-methylmorpholine-1,4-methylmorpholine HMPA =hexamethylphosphoric triamide DMPU = 1,3-dimethypropylene urea d = daysppm = parts per million kD = kiloDalton LPS = lipopolysaccharide PMA =phorbol myristate acetate SPA = scintillation proximity assay EDTA =ethylenediamine tetraacetic acid FBS = fetal bovine semm PBS = phosphatebuffered saline solution BrdU = bromodeoxyuridine BSA = bovine serumalbumin FCS = fetal calf serum DMEM = Dulbeccols modified Eagle's mediumpfu = plaque forming units MOI = multiplicity of infection

Reagents are commercially available or are prepared according toprocedures in the literature. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds. ¹H NMR spectra were obtained on VARIAN Unity Plus NMRspectrophotometers at 300 or 400 Mhz. Mass spectra were obtained onMicromass Platform II mass spectrometers from Micromass Ltd. Altrincham,UK, using either Atmospheric Chemical Ionization (APCI) or ElectrosprayIonization (ESI). Analytical thin layer chromatography (TLC) was used toverify the purity of some intermediates which could not be isolated orwhich were too unstable for full characterisation, and to follow theprogess of reactions. Unless otherwise stated, this was done usingsilica gel (Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds, used Merck Silicagel 60 (230-400 mesh), and the stated solvent system under pressure.

Procedure A—First method for 1H-indol-2,3-dione (isatin) formation:preparation of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione

To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate,and 100 mL of water. The mixture was magnetically stirred until all thesolids were dissolved. To the resultant aqueous solution was added asolution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1Naqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred,and chloral (6.0 g, (36 mmol) was added. To the resultant solution wasadded a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in30 mL of water. The final mixture was heated with stirring to a gentleboil until all solids dissappeared, and heating was continued for anadditional 15 min. The flask was removed from the heat, and the solutionwas poured onto 500 g of ice. The mixture was stirred as the productprecipatated from solution. The precipatate was collected by suctionfiltration, washed thoroughly with water, filtered, and air dried toprovide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: ¹HNMR (DMSO-d₆): δ 12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H),7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI-MS m/z 220 (M−H)⁻. To a 1-L3-neck round bottom flask was placed a magnetic stir bar and 100 ml ofconcentrated sulfuric acid. The flask was fitted with a thermometer tomonitor the temperature of the reaction. The sulfuric acid was heated to100° C., and 10.0 g (45.2 mmol) ofN-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. Thesolution was heated for ˜1 h, and the reaction mixture was poured into750 g of ice and water. The residual reaction mixture in the reactionvessel was washed out with an additional 20 mL of cold water. Theaqueous slurry was stirred for about 1 h and filtered. The solid waswashed thoroughly with water, filtered, and air dried to yield 4.3 g(46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: ¹H NMR (DMSO-d₆): δ11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI-MS m/z 203(M−H)⁻.

Procedure B—First method for 1,3-dihydro-indol-2-one (oxindole)formation (Gassman and van Bergen, Journal of the American ChemicalSociety 1974, 96, 5508-12): preparation of 6.8-dihydro-1-thia-3,6-diaza-as-indacen-7-one

A 2-L three-neck round bottom flask was fitted with an internalthermometer, 250-mL addition funnel, magnetic stir bar and septa. Theflask was charged with nitrogen, 200 mL of dry THF, and6-aminobenzothiazole (15.2 g, 0.100 mol). The mixture was stirred andcooled in a dry ice-acetone bath to an internal temperature of −74° C. Asolution of tert-butyl hypoclorite (11.0 g, 0.103 mol) in 50 mL ofdichloromethane was added over a 15 min period. The resultant solutionwas stirred for an additional 3 h at dry ice-acetone bath temperature.To the reaction was then added by slow, dropwise addition a solution ofethyl methylthioacetate (13.8 g, 0.103 mol) in 50 mL of dichoromethane.The resultant solution was stirred for an additional 3 h at dryice-acetone bath temperature. A solution of triethyl amine (25.3 g,0.250 mol) and 50 ml of dichloromethane was added at dry ice-acetonebath temperature, and the solution was stirred for 0.5 h. The coolingbath was removed, and the reaction was allowed to warm to rt. Thereaction was then concentrated to a thick residue. The thick oil wasresuspended in 200 mL of ether and 600 mL of 0.25 M hydrochloric acid.The mixture was allowed to stir for 24 h. The resulting solid wasfiltered from the mixture and triturated with water and ether. The solidwas then resuspended in cold MeOH, filtered and dried under vacum for 16h to yield 18.7 g (79%) of8-methylsulfanyl-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one: ₁H NMR(DMSO-d6) δ 10.8 (s, 1H), 9.2 (s, 1H), 8.0 (d, 1H), 7.1 (d, 1H), 1.8 (s,3H); APCI-MS m/z 235 (M−H)−. To a 500-mL erlenmeyer flask was added astir bar, 8.1 g (0.034 moles) of8-methylsulfanyl-6,8-dihydro-1-thio-3,6-diaza-as-indacen-7-one and 100mL of glacial acetic acid. The mixture was stirred until all thestarting material had dissolved. The reaction mixture was then dilutedwith 100 mL of THF. Zinc metal (16 g, 325 mesh) was then added. Theheterogeneous mixture was then stirred and heated to 60° C. for 2.5 h.The mixture was vacuum filtered through a one half inch pad of celite.The residue on the filter pad was washed with additional THF. Thefiltrates were combined and concentrated to a wet solid. The solid wastriturated with MeOH, filtered and air dried to yield 4.51 g (70%) of6.8-dihydro-1-thia-3,6diaza-as-indacen-7-one as a free-flowing solid: ₁HNMR (DMSO-d6): δ 10.5 (s, 1H), 9.1 (s, 1H), 7.9 (d, 1H), 7.0 (d, 1H),3.6 (s, 2H); APCI-MS m/z 191 (M+H)₊.

Procedure C—Second method for 1,3-dihydro-indol-2-one (oxindole)formation (Seibert, Chemie Berichte 1947, 80, 494-502): preparation of3-H-pyrrolo[3,2-f]quinoline-2one via Wolff-Kishner reduction

A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione(prepared from 6-aminoquinoline according to Procedure A) and 2.0 ml(0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirredat reflux for 2 h. The resulting suspension was allowed to cool toambient temperature and was then chilled in an ice bath and filtered.The solid was washed with a small volume of ethanol and allowed to airdry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as anorange solid (1.8 g, 73%): ¹H NMR (DMSO-d₆): δ 7.37 (d, J=8.8 Hz, 1H),7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2,1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89(br d, J=14.7 Hz, 1H), 10.95 (br s, 1H); ESI-MS m/z 213 (M+H)⁺. Asolution 1.8 g (8.5 mmol) of1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshlyprepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 h.The solution was diluted with 50 ml of water, neutralized with aceticacid, and concentrated on a rotary evaporator until cloudy. The solutionwas stored in a refrigerator overnight. The solid was filtered off, andthe filtrate was extracted with three 80-ml portions of EtOAc. Asolution of the solid in MeOH/EtOAc was combined with the extracts andpassed through a short pad of silica gel, eluting with EtOAc. Thesolution was then concentrated to a small volume on a rotary evaporator,and the resulting suspension was diluted with an equal volume ofethanol, sonicated, and filtered to give3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%);¹H NMR (DMSO₆): δ 3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4,4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd,J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCI-MS m/z 183 (M−H)⁻.

Procedure D—Third method for 1,3-dihydro-indol-2-one (oxindole)formation (Quallich and Morrissey, Synthesis, 1993, 51-53): preparationof 6-bromooxindole

Sodium hydride (60% oil dispersion, 4.00 g, 100 mmol) was added to a dry500 ml flask under nitrogen and washed with three 25 ml portions ofhexanes. Anhydrous DMSO (100 ml) was added, followed by dimethylmalonate (11.4 ml, 100 mmol). The reaction was heated briefly to 100° C.with stirring, then cooled to room temperature. 2,5-Dibromonitrobenzene(12.9 g, 46.0 mmol) was added and the reaction was heated at 110° C. for2 hrs. After cooling to room temperature, the solution was added inportions to 300 ml of saturated aqueous ammonium chloride with 150 ml of1:1 hexanes/ethyl acetate. The organic layer was washed with 300 ml ofsaturated aqueous ammonium chloride, four 200 ml portions of water, and200 ml of saturated aqueous sodium chloride. The organic layer was driedover magnesium sulfate and the solvent was evaporated to give 13.6 g ofcrude dimethyl 2-(4-bromo-2-nitrophenyl)malonate as a brown oil. Thismaterial (30-40 mmol) was heated to 110° C. in 250 ml DMSO with 3.6 g(84 mmol) of lithium chloride and 750 mg (42 mmol) of water for 4.5 hrs.The reaction was cooled to room temperature and added to 300 ml of ethylacetate with 300 ml of saturated aqueous sodium chloride. The organiclayer was washed with a second portion of 300 ml saturated aqueoussodium chloride, dried over magnesium sulfate, and the solvent wasremoved to give 11.1 g brown oil. This material was adsorbed on 40 g ofsilica gel and applied to a column containing another 80 g of silicagel. Elution with 0-10% ethyl acetate in hexanes gave 3.53 g (28% from2,5-dibromonitrobenzene) of methyl (4-bromo-2-nitrophenyl) acetate as ayellow solid.

This material (3.53 g, 12.8 mmol) was dissolved in ethanol (80 ml) with50 ml of 50% sulfuric acid and heated to reflux with stirring. Zincpowder (3.40 g, 52 mmol) was added in portions over 1 hr. Heating wascontinued for another 2 hrs and the reflux condenser was removed toallow ethanol to evaporate from the hot reaction under a stream ofnitrogen. The reaction mixture was filtered through celite, washing with100 ml of ethyl acetate. The water layer was separated from the filtrateand extracted with 100 ml of ethyl acetate. Combined ethyl acetatelayers were washed with 30 ml of saturated aqueous sodium bicarbonateand 30 ml of saturated aqueous sodium chloride and dried over magnesiumsulfate. Evaporation of solvent gave 1.6 g of crude product which waspurified by chromatography on 25 g of silica gel with 10-40% ethylacetate/hexanes to give 0.85 g (31%) of 6-bromooxindole as an off-whitesolid.

Procedure E—Method for dimethylaminomethinyloxindole formation:preparation of8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one

To a suspension of 1.0 g (5.3 mmol) of6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure B) in 7.5 mL ofDMF was added 1.38 g (6.80 mmol) of N,N-dimethylformamide-di-t-butylacetal. The mixture was stirred at ambient temperature for 1 h anddiluted with 7.5 mL of Et₂O. The resulting precipitate was isolatedfiltration to afford8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-oneas a tan solid (1.0 g, 77%): ¹H NMR (DMSO-d₆): δ3.33 (bs, 3H), 3.59 (bs,3H), 6.97 (d, J=8.4, 1H), 7.33 (s, 1H), 7.62 (d, J=8.4, 1H), 9.13(s,1H), 10.29 (s, 1H); APCI-MS: m/z 246 (M+H)⁺.

Procedure F—Method for ethoxymethinyloxindole formation: preparation of8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one

To a 250-ml round bottom flask was added a stir bar,6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure B, 4.0 g, 0.021mol), 40 mL of glacial acetic and diethoxymethyl acetate (17.0 g, 0.105moles). The flask was fitted with a reflux condensor and charged withnitrogen. The reaction was heated to reflux for 8 h. The flask wascooled, the stir bar was removed and the reaction was concentrated to awet solid. The solid was triturated with a solution of ether andethanol. The mixture was filtered, the solid was washed with anethanol-ether solution, and the solid was dried under vacuum to yield8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one: ¹H NMR(DMSO-d₆): δ 10.5 (s, 1H), 9.1 (s, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.0(d, 1H), 4.5 (q, 2H), 1.4 (t, 3H); APCI-MS m/z 245 (M−H)⁻.

Procedure G—Method for vinylogous urea formation: preparation ofN-methyl-N-(4-{(Z)-[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}phenyl)acetamide(Example 58)

A mixture of8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one(Procedure E, 0.040 g, 0.163 mmol) or8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one(Procedure F, 0.163 mmol), 4-amino-N-methylacetanilide (0.040 g, 0.244mmol) in absolute ethanol (5 ml) was heated with stirring at 90° C. for16 h. The reaction was diluted with ethanol and diethyl ether and theproduct collected by filtration to yield 0.038 g (64%) of the titlecompound. ¹H NMR (DMSO-d₆): δ 11.03 (d, 1H, J=12.3 Hz), 10.84 (s, 1H),9.23 (s, 1H), 8.02 (d, 1H, J=12.3 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.48(d,2H, J=8.2 Hz), 7.35 (d,2H, J=8.2 Hz), 7.09 (d, 1H, J=8.4 Hz), 3 .11(s,3H), 1.76 (s, 3H); ES-MS m/z 363 (M−H).

Procedure H—Method for condensation of a phenylhydrazine with an isatinto form hydrazones: preparation of3,6-dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-[N-(4-methoxyphenyl)hydrazone] (Example 89)3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione was prepared from5-aminobenzotrazole according to Procedure A in 6% yield: ¹H NMR(DMSO-d₆): δ 7.04 (d, J=8.4 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 8.01 (dd,J=2.2, 8.4 Hz, 1H), 8.20 (s, 1H), 9.26 (s, 1H), 11.19 (bs, 1H); APCI-MSm/z 215 (M+1)⁺. 3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione (47mg, 0.25 mmol) was combined with 4-methoxyphenylhydrazine hydrochloride(52 mg, 0.3 mmol) in 2 ml of ethanol and heated at 70° C. for 3 hrs. Theproduct was collected by filtration of the hot solution, washing withethanol and diethyl ether, to give 39 mg (50%) of the title compound asa dark red solid. NMR showed ˜1:1 Z/E mixture. ¹H NMR (DMSO-d₆): 67 3.80(s, 3H); 7.0 (m, 3H); 7.24 (d, J=8.7 Hz, 0.5H); 7.41 (d, J=8.8 Hz,0.5H); 7.78 (m, 1.5H); 7.98 (d, J=8.5 Hz, 0.5H); 10.8 (s, 0.5H); 11.3(s, 0.5H); 12.85 (s, 0.5H); 12.95 (s, 0.5H). APCI-MS m/z 307 (M−1)Procedure I—Method for palladium catalyzed coupling of 6-bromooxindolewith alkenyl and aromatic tin reagents: preparation of 6-vinyl oxindole

To a mixture of 6-bromooxindole (Procedure D, 0.50 g, 2.4 mmol),vinyltributylstannane (0.95 g, 3.0 mmol), lithium chloride (0.03 g, 7.1mmol), 2,6-di-tert-butyl-4-methylphenol (0.01 g, 0.05 mmol) inacetonitrile (25 ml) stirring at 80° C. was addeddichlorobis(triphenylphosphine)palladium (II). The resulting reactionwas stirred with heating for 16 h. The reaction was poured into avigorously stirring mixture of 5M potassium fluoride solution: ethylacetate/1:1 (250 mL) and stirred for 0.75 h. The resulting biphashicmixture was filtered through a Celite 521 pad and the pad flushed withethyl acetate (5×200 mL). The combined organic phases were washed withwater (200 mL), saturated sodium chloride (200 mL) and filtered throughWhatman PS 1 paper and evaporated in vacuo to a golden yellow syrup. Thesyrup was titurated with diethyl ether to yield several crops of tansolid. Pure samples were combined, slurried with diethyl ether,filtered, and air dried to yield 0.12 g (31%) of 6-vinyloxindole: ¹H NMR(DMSO-d₆): 67 10.36 (s,1H), 7.13 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=7.5Hz), 6.66 (dd,1H, J=10.9, 17.7 Hz), 5.70 (d, 1H, J=17.6 Hz), 5.18 (d,1H, J=10.9 Hz), 3.42 (s,2H).

EXAMPLE 1 6-Bromo-3-{(Z andE)-[4-(4-morpholinyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared from the dimethylaminomethylene derivative (Procedure E) of6-bromo-oxindole (procedure D) and 4-(4-morpholino)aniline according toProcedure G in 87% yield to give ˜4:1 isomer mixture. Principal isomer:¹H NMR (DMSO-d₆): δ 10.67 (d, 1H, J=12.5 Hz), 10.56 (s, 1H), 8.57 (d,1H, J=12.8 Hz), 7.48 (d, 1H, J=7.9 Hz), 7.35-7.29 (m,2H), 7.11 -7.04 (m,3H), 6.93 (s, 1H), 3.76 (s, 4H), 3.15 (s, 4H); ES-MS m/z 400, 402 (M+1).

EXAMPLE 2 6-Bromo-3-{(Z andE)-[4-(4-pyridinylmethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared according to Example 1 in 26% yield to give ˜9:1 isomermixture. Principal isomer: ¹H NMR (DMSO-d₆): δ 10.72 (d, 1H, J=12.6 Hz),10.65 (s, 1H), 8.66 (d, 1H, J=12.8 Hz), 8.48 (d, 1H, J=5.9 Hz), 7.55 (d,1H, 8.1 Hz), 7.40-7.27 (m, 6H), 7.12 (dd, 1H, J=1.8, 8.1 Hz), 6.99 (d,1H, J=1.8 Hz), 3.97 (s, 2H); APCI-MS m/s 404, 406 (M−1).

Example 3 8-[(Z andE)-4-Toluidinomethylidene]-6,8-dihydroimidazo[4,5-e]indol-7(3H)-one.

Sodium hydride (7.2 g, 60% in mineral oil, 0.18 mol) was added inportions over 30 min to a stirred solution of 5-aminobenzimidazole (15.0g, 0.105 mol) in dry DMF (100 mL) and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C. and asolution of di-tert-butyl dicarbonate (24.0 g, 0.110 mol) in dry DMF (25mL) was added over 10 min. The reaction mixture was stirred at roomtemperature for 18 h. The solvent was evaporated under reduced pressureand the residue was partitioned between water (200 mL) and diethyl ether(200 mL). The organic phase was separated and the aqueous layer wasextracted with diethyl ether. The combined organic extracts were washedwith water and brine and dried over anhydrous magnesium sulfate. Thedrynig agent was removed by filtration through a pad of silica gel andthe filtrate evaporated to give a mixture of 5- and6-amino-1-tert-butoxycarbonylbenzimidazole, 21.5 g (84%). H¹ NMR(DMSO-d₆): δ 8.40 (s, 1H), 8.23 (s, 1H), 7.55 (d, 1H, J=8.8 Hz), 7.34(d, 1H, J=8.4 Hz), 7.13 (d, 1H, J=1.6 Hz), 6.83 (d, 1H, J=2 Hz), 6.68(dd, 1H, J=8.8, 1.6 Hz), 6.60 (dd, 1H, J=8.4, 2 Hz), 1.61 (s, 9H), 1.60(s, 9H).

To a cold (−78° C.) solution of ethyl methylthioacetate (11.87 g, 88mmol) in dry dichloromethane (300 mL) was added, dropwise, sulfurylchloride (7.1 mL, 11.93 g, 88 mmol) over 5 min. The solution was stirredfor 30 min and then a solution of a mixture of 5- and6-amino-1-tert-butoxycarbonylbenzimidazole (21.5 g, 88 mmol) and ProtonSponge (18.9 g, 88 mmol) in dry dichloromethane (150 mL) was addeddropwise over 30 min. The mixture was stirred at ñ78° C. for about 1 hand then triethylamine (12.3 mL, 8.94 g, 88 mmol) was added dropwise andthe mixture was allowed to warm to room temperature over 18 h. Thereaction mixture was washed with water (3×100 mL) and brine and then theorganic phase was dried over anhydrous magnesium sulfate. The dryingagent was removed by filtration through a pad of silica gel and thefiltrate evaporated. The residue was triturated with a small amount ofdiethyl ether and the resulting solid was collected by filtration. Thefiltrate was stirred with 2N aqueous HCl (10 mL) for 18 h to yieldfurther white solid which was collected by filtration. The combinedwhite solids were dried under vacuum to give a mixture of 1 and3-tert-butoxycarbonyl-8-methylthio-7-oxo-7,8-dihydropyrrolo[2,3-g]benzimidazole,8.74 g (30%). H¹ NMR (DMSO-d₆): δ 10.882 (s, 1H), 10.72 (s, 1H), 9.41(s, 1H), 8.52 (s, 1H), 7.45 (d, 1H, J=8.4 Hz), 7.65 (d, 1H, J=8.4 Hz),7.11 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.4 Hz), 4.84 9s, 1H), 4.67 (s,1H), 1.93 (s, 3H), 1.81 (s, 3H), 1.66 (s, 9H).

A solution of a mixture of 1 and 3-tert-butoxycarbonyl-8methylthio-7-oxo-7,8-dihydropyrrolo[2,3-g]benzimidazole (2.0 g, 6 mmol)in THF (50 mL) was stirred at room temperature and a saturated aqueoussolution of ammonium chloride (50 mL) was added. Activated zinc dust(8.0 g) was added and the resulting mixture was stirred vigorously forabout 18 h. The solids were removed by filtration through a pad ofCelite and the organic layer was separated. The organic phase was driedover anhydrous magnesium sulfate, filtered and the solvent evaporatedunder reduced pressure to leave a yellow solid. Trituration with a smallamount of solid gave a pale solid which was collected by filtration anddried under vacuum to give a mixture of 1 and3-tert-butoxycarbonyl-7-oxo-7,8-dihydropyrrolo[2,3-g]benzimidazole, 1.32g (77%). H¹ NMR (DMSO-d₆): δ 10.51 (br s, 1H),10.21 (br s, 1H), 8.46 (s,1 h), 8.02 (s, 1H), 7.67 (m, 1H), 7.55 (d, 1H), 6.87 (d, 1H), 6.70 (m,1H), 3.84 (s, 2H), 1.62 (s, 9H).

Dimethylformamide di-tert-butyl acetal (0.34 mL, 0.29 g, 1.4 mmol) wasadded dropwise to a stirred solution of a mixture of 1 and3-tert-butoxycarbonyl-7-oxo-7,8-dihydropyrrolo[2,3-g]benzimidazole (0.2g, 0.7 mmol) in dry DMF (2 mL) and the mixture was stirred at roomtemperature for about 6 h. The solvent was evaporated under reducedpressure. The residue was dissolved in chloroform:methanol (10:1, 10 mL)and passed through a pad of silica gel. The filtrate was evaporated togive a mixture of 1 and3-tert-butoxycarbonyl-8-(dimethylaminomethylidinyl)-7-oxo-7H-pyrrolo[2,3-g]benzimidazoleas a brown solid, 0.042 g (17%). ¹H NMR (DMSO-d₆): δ 10.10 (s, 1H), 8.40(s, 1H), 7.40 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 6.82 (d, 1H, J=8.4 Hz),1.64 (s, 9H).

A solution of a mixture of 1 and3-tert-butoxycarbonyl8-(dimethylaminomethylidinyl)-7-oxo-7H-pyrrolo[2,3-g]benzimidazole(0.02 g, 0.061 mmol) and p-toluidine (0.01 g, 0.089 mmol) in acetic acid(1 mL) was heated at 120° C. for 3 h. The solvent was evaporated undervacuum and the residue was purified using silica gel chromatography withchloroform:methanol (10:1) as eluent to afford the title compound as amixture of E/Z isomers, 0.012 g (68%). ¹H NMR of principal isomer(DMSO-d₆): δ 12.57 (s, 1H), 12.38 (d, 1H, J=12.8 Hz), 10.01 (s, 1H),8.33 (s, 1H), 7.95 (d, 1H, J=12.8 Hz), 7.24 (m, 5H), 6.80 (d, 1H, J=8Hz), 2.28 (s, 3H). MS (AP⁻) 289 (100) (M⁺−H).

EXAMPLE 4 8-[(Z andE)-(3-Methyl-4-nitroanilino)methylidene]3,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one

Prepared as a 1:1 mixture of Z and E isomers in 95% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand 3-methyl4-nitroaniline according to the procedure of Example 5. ¹HNMR (DMSO-d₆): δ 2.65 (s, 6H); 7.07 (d, J=8.5 Hz, 0.5H); 7.18 (d, J=8.5Hz, 0.5H); 7.44 (dd, J=9.0 Hz and 1.5 Hz, 0.5H); 7.53 (m, 1H); 7.6 (m,1H); 7.78 (brd d, J=8.2 Hz, 0.5H); 8.17 (d, J=9.0 Hz, 0.5H); 8.19 (d,J=9.5 Hz, 0.5H); 8.29 (brd d, J=12.6 Hz, 0.5H) 8.70 (d, J=12.1 Hz,0.5H); 10.49 (s, 0.5H); 11.0 (s, 0.5H); 11.16 (d, J=12 Hz, 0.5H); 11.8(brd d, J˜8 Hz, 0.5H). APCI-MS: m/z 335 (M−H)⁻.

EXAMPLE 58-{(E/Z)-[4-nitro-3(trifluoromethyl)anilino]methylidene}-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one

5-Aminobenzotriazole (Lancaster Chemical, 10.14 g, 75 mmol) wasdissolved in 200 ml of anhydrous DMF under nitrogen and 3.00 g (75 mmol)of sodium hydride (60% oil dispersion) was added in one portion.Hydrogen evolution and mild exothermicity was observed. The reaction wasstirred at room temperature for 20 minutes and then cooled in an icebath. A solution of di-tert-butyidicarbonate (16.4 g, 75 mmol) in 100 mlof anhydrous DMF was added via siphon. Stirring was continued for 2 hrsat ice bath temperature. The solvent was removed by rotary evaporationunder high vacuum at 50 ° C. to give 32 g of viscous liquid. The crudeproduct was dissolved in a minimum volume of chloroform and filteredthrough a short column of 600 ml silica gel, eluting with 10% methanolin chloroform. The collected product was evaporated to dryness,redissolved in 400 ml of diethyl ether, and washed three times withwater and once with saturated sodium chloride solution. The ethersolution was dried over magnesium sulfate and the solvent was removed togive 17.7 g of a mixture of 1- and3-tert-butyloxycarbonyl-5-aminobenzotriazole contaminated with approx. 1g of residual mineral oil. This material was then cyclized to thecorresponding 3-methylthio-oxindole by the method of Procedure(Gassman). The resultant product (9.6 g of gray solid) was shown to bepartially deprotected by NMR. This material was dissolved 200 ml of THFand treated with 50 g of zinc dust (activated by stirring for 10 min in150 ml of 1 M HCl, followed by washing with three 100 ml portions ofwater). Saturated aqueous ammonium chloride (150 ml) was added and thereaction was stirred overnight at room temperature. The solution wasfiltered through Celite, washing with THF and ethyl acetate to give 4.0g of gray solid which was primarily1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7one.This material (2.04 g, 7.4 mmol) was suspended in 10 ml of anhydrous DMFunder nitrogen, cooled in an ice bath, and treated with 4.0 ml (3.4 g,2.2 equiv) of dimethylformamide di-tert-butyl acetal. The reaction wasallowed to warm to room temperature and was stirred overnight. Thesolvent was removed by rotary evaporation under high vacuum. The residuewas filtered through a short column of 100 ml silica gel with 30%ethanol in dichloromethane. Evaporation of solvent provided 1.74 g ofyellow solid which was primarily8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-onecontaining some product lacking the tert-butyloxycarbonyl protectinggroup.

The dimethylamino-oxindole derivative from above (33 mg, ˜0.1 mmol) wascombined in a reaction vial with 4-nitro-3-trifluoromethylaniline (25mg, 0.12 mmol) in 1-2 ml of glacial acetic acid and stirred overnight inan oil bath at 110° C. The residue was triturated with 2 ml of ethanol,heating briefly to reflux. After cooling to room temperature, 2-3 ml ofdiethyl ether was added and the resulting precipitate was collected byfiltration to give 7.8 mg (20%) of the title compound as a brown solidthat was shown by NMR to be ˜1:1 mixture of E/Z isomers. ¹H NMR(DMSO-d₆): δ 7.07 (d, J=9 Hz, 0.5H); 7.20 (d, J=8 Hz, 0.5H); 7.63 (d,J=8 Hz, 0.5H); 7.8 -8.0 (m, 2H); 8.13 (s, 0.5H); 8.25-8.42 (m, 1.5H);8.67 (d, J=11 Hz, 0.5H); 10.53 (s, 0.5H); 11.0 (s, 0.5H); 11.24 (d, J=11Hz); 12.0 (brd d, J˜9 Hz, 0.5H). APCI-MS: m/z 389 (M−H)⁻.

EXAMPLE 6 8-[(Z andE)-(3-Chloro-4-nitroanilino)methylidene]-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one

Prepared as a ˜1:1 mixture of Z and E isomers in 70% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand 3-chloro-4-nitroaniline according to the procedure of Example 5. ¹HNMR (DMSO-d₆): δ 7.06 (d, J=8.8 Hz, 0.5H); 7.20 (d, J=8.5 Hz, 0.5H);7.3-7.66 (m, 1.5H); 7.80 (brd m, 0.5H); 7.85 (d, J=2.5 Hz, 0.5H); 7.91(d, J=2.5 Hz, 0.5H); 8.23 (d, J=9.1 Hz, 1H); 8.32 (brd m, 0.5H); 8.63(d, J=11.7 Hz, 0.5H); 10.5 (s 0.5H); 11.0 (s, 0.5H); 11.1 (d, J=11.7 Hz,0.5H); 11.8 (brd, 0.5H). APCI-MS: m/z 355 (M−H)⁻.

EXAMPLE 7 8-[(Z andE)-(3,5-Dimethyl-4-nitroanilino)methylidene]-1,6-dihydro[1,2,3,]triazolo[4,5-e]indol-7-one

Prepared as a ˜1:1 mixture of Z and E isomers in 74% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand 3,5-dimethyl-4-nitroaniline according to the procedure of Example 5.¹H NMR (DMSO-d₆): δ 2.36 (s, 6H); 7.07 (d, J=8.5 Hz, 0.5H); 7.17 (d,J=8.5 Hz, 0.5H); 7.37 (s, 2H); 7.57 (d, J=8.5 Hz, 0.5H); 7.76 (brd d,J=8.5 Hz, 0.5H); 8.24 (brd d, J=12 Hz, 0.5H); 8.69 (brd d, J=12 Hz,0.5H); 10.44 (s, 0.5H); 10.97 (s, 0.5H); 11.07 (brd d, J=12 Hz, 0.5H);11.6 (brd d, J=12 Hz, 0.5H). APCI-MS: m/z 349 (M−H)⁻.

EXAMPLE 8 8-((Z andE)-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]anilino}methylidene)-1,6-dihydro[1,2,3,]triazolo[4,5-e]indol-7-one

The title compound was prepared as a ˜1:1 mixture of Z and E isomers in54% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]anilineaccording to the procedure of Example 5. ¹H NMR (DMSO-d₆): δ 7.07 (d,J=8.7 Hz, 0.5H); 7.17 (d, J=8.7 Hz, 0.5H); 7.56 (d, J=8.7 Hz, 0.5H); 7.6and 7.75 (2 overlapping Abq, 4H); 8.22 (d, J=13 Hz, 0.5H); 8.75 (m, 1H);10.4 (s, 0.5H); 10.9 (s, 0.5H); 11.08 (d, J=13 Hz, 0.5H); 11.7 (brd d,J=13 Hz, 0.5H). APCI-MS: m/z 442 (M−H)⁻.

EXAMPLE 9 8{(Z andE)-[4-(2-Hydroxyethyl)anilino]methylidene}-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-one

The acetate ester of the title compound was obtained as a ˜1:1 mixtureof Z and E isomers in 71% yield (26 mg) from 8-dimethylaminomethylene-1tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5e]indol-7-one (25mg) and 4-(2-hydroxyethyl)aniline (17 mg) in acetic acid according tothe procedure of Example 5. The product was stirred in 4 ml methanolwith 0.2 ml of 2M NaOH overnight at room temperature. The reactionsolution was acidified with 0.2 ml of 2M sulfuric acid, and ethanol anddiethyl ether were added. The resulting precipitate was collected byfiltration and stirred in 3 ml of water for several hours to dissolveNa₂SO₄, then filtered and dried to give the title compound (16 mg darkgreen solid, 70%). ¹H NMR (DMSO-d₆): δ 2.69 (t, J˜6 Hz, 2H); 3.58 (m,2H); 4.62 (m, 1H); 7.01 (d, J=8.5 Hz, 0.5H); 7.12 (d, J=8.5 Hz, 0.5H);7.26 and 7.32 (overlapping Abq, 4H); 7.46 (d, J=8.5 Hz, 0.5H); 7.64(brd, 0.5H); 8.13 (d, J=13 Hz, 0.5H); 10.3 (s, 0.5H); 10.8 (s, 0.5H);11.0 (d, J=13 Hz, 0.5H); 11.45 (brd, 0.5H). APCI-MS: m/z 320 (M−H)⁻.

EXAMPLE 108-{(Z)-[4-(Methylsulfanyl)anilino]methylidene}-6H-[1,3]thiazolo[5,4-e]indol-7-one

This compound was prepared with 4-methylthioaniline according toProcedure G on a 0.5 mmol scale. The yield was 0.089 grams (53%) forC₁₇H₁₃N₃O₁S₂.

¹H NMR (400 MHz, DMSO-d₆) δ : 10.9(d, 1H), 10.78(s, 1H), 9.21(s, 1H),7.9(d, 1H), 7.7(d, 1H), 7.25(d, 2H), 7.1(d, 1H), 6.8(d, 2H), 2.4(s, 3H).ESI-MS m/z 338(M−1).

EXAMPLE 118-[(Z)-(3,5-Dimethoxyanilino)methylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one

This compound was prepared 3,5-dimethoxyaniline according to Procedure Gon a 0.5 mmol scale. The yield was 0.076 grams (43%) for C₁₈H₁₅N₃O₃S₁.

¹H NMR (400 MHz, DMSO-d₆) 67 : 10.9(d, 1H), 10.83(s, 1H), 9.21(s, 1H),7.98(d, 1H), 7.77(d, 1H), 7.08(d, 1H), 6.59(s, 2H), 6.25(s, 1H), 3.77(s,6H). ESI-MS m/z 352(M−1).

EXAMPLE 128[(Z)-(4-Hydroxyanilino)methylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one

This compound was prepared with 4-hydroxyaniline according to ProcedureG on a 0.5 mmol scale. The yield was 0.081 grams (53%) for C₁₆H₁₁N₃O₂S₁.

¹H NMR (400 MHz, DMSO-d₆) δ : 10.95(d, 1H), 10.75(s, 1H), 9.42(s, 1H),9.2(s, 1H), 7.91(d, 1H), 7.72(d, 1H), 7.23(d, 2H), 7.07(d, 1H), 6.79(d,2H). ESI-MS m/z 308(M−1).

EXAMPLE 131-[(Z)-(3-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared from the dimethylaminomethylene derivative (Procedure E) of1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one (Procedure C) with3-methoxyaniline according to Procedure G to give the title compound in63% yield. ¹H NMR (DMSO-d₆) δ : 3.80 (s, 3H); 6.68 (dd, J=1.8, 8.2 Hz,1H); 7.06 (brd d, J=8.0 Hz, 1H); 7.11 (brd s, 1H); 7.29 (t, J=8.1 Hz,1H); 7.40 (d, J=8.8 Hz, 1H); 7.46 (dd, J=8.5, 4.1 Hz, 1H); 7.71 (d,J=8.8 Hz,1H); 8.70 (d, J=4.1 Hz, 1H); 8.8 (2 overlapping d, J=8.5, 12Hz, 2H); 10.94 (s, 1H); 11.74 (d, J=12 Hz, 1H). ES-MS: m/z 316 (M−H)⁻.

EXAMPLE 143-{[(Z)-(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzonitrile

Prepared from the dimethylaminomethylene derivative (Procedure E) of1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one (Procedure C) with3-aminobenzonitrile according to Procedure G in acetic acid to give thetitle compound in 78% yield as the acetate salt. ¹H NMR (DMSO-d₆) δ :1.88 (s, 3H); 7.39 (d, J=8.5 Hz, 1H); 7.45-7.6 (m, 3H); 7.78 (m, 2H);8.20 (s, 1H); 8.75 (d, J=4 Hz, 1H); 8.8-8.9 (m, 2H); 11.0 (s, 1H); 11.8(d, J=12 Hz, 1H); 11.95 (s, 1H). ES-MS: m/z 313 (M+H)⁺.

EXAMPLE 151-[(Z)-4-Toluidinomethylidene]-1,3dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared from the dimethylaminomethylene derivative (Procedure E) of1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one (Procedure C) withp-toluidine according to Procedure G to give the title compound in 98%yield. ¹H NMR (DMSO-d₆) δ : 2.25 (s, 3H); 7.2 (m, 2H); 7.35-7.5 (m, 4H);7.70 (d, J=8.5 Hz, 1H); 8.70 (d, J=4.0 Hz, 1H); 7.8 (m, 2H); 10.9 (s,1H); 11.8 (d, J=12 Hz, 1H). ES-MS: m/z 302 (M+H)⁺.

EXAMPLE 161-[(Z)-(4-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared from the dimethylaminomethylene derivative (Procedure E) of1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one (Procedure C) with4-methoxyaniline according to Procedure G in acetic acid to give thetitle compound in 54% yield as the acetate salt. ¹H NMR (DMSO-d₆) δ :1.88 (s, 3H); 3.75 (s, 3H); 6.97 (d, J=8.9 Hz, 2H); 7.39 (d, J=8.7 Hz,1H); 7.43-7.5 (m, 3H); 7.68 (d, J=8.5 Hz, 1H); 8.70 (d, J=4.0 Hz, 1H);8.75-8.82 (m, 2H); 10.9 (s, 1H); 11.75 (d, J=12 Hz, 1H); 11.9 (s, 1H).ES-MS: m/z 318 (M+H)⁺.

EXAMPLE 17 3-({[(Z andE)-7-Oxo-6,7-dihydro[1,2,3]triazolo[4,5-e]indol-8(1H)-ylidene]methyl}amino)benzonitrile

Prepared as a ˜3:2 mixture of geometrical isomers in 88% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand 3-aminobenzonitrile according to the procedure of Example 5. ¹H NMR(DMSO-d₆): δ 6.88 and 7.02 (2 d, 3:2 ratio, J=8.7 Hz, 1H); 7.45-7.6 (m,˜2.6H); 7.65-7.8 (m, ˜1.4H); 7.90 and 7.95 (2 s, 1H); 8.15 and 8.83 (2s, 1H); 10.2 and 10.85 (2 s, 1H). ES-MS: m/z 303 (M+H)⁺.

EXAMPLE 18 8-[(Z andE)-4-Toluidinomethylidene]-1,6-dihydro[1,2,3,]triazolo[4,5-e]indol-7-one

Prepared as a ˜1:1 mixture Z and E isomers in 78% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand p-toluidine according to the procedure of Example 5. ¹H NMR(DMSO-d₆): δ 2.28 (s, 3H); 7.01 and 7.11 (2 d, 1:1 ratio, J=8.4 Hz, 1H);7.22 and 7.32 (2 overlapping ABq, 4H); 7.45 and 7.64 (2 d, 1:1 ratio,J=8.4 Hz, 1H); 8.11 and 8.68 (2 d, 1:1 ratio, J=13 Hz, 1H); 10.3 and10.8 (2 s, 1:1 ratio, 1H); 11.0 and 11.45 (2 d, 1:1 ratio, J=13 Hz, 1H).ES-MS: m/z 292 (M+H)⁺.

EXAMPLE 19 8-[(Z andE)-(4-Methoxyanilino)methylidene]-1,6-dihydro[1,2,3,]triazolo[4,5-e]indol-7-one

Prepared as a ˜1:1 mixture Z and E isomers in 88% yield from8-dimethylaminomethylene-1-tert-butyloxycarbonyl-1,6-dihydro[1,2,3]triazolo[4,5-e]indol-7-oneand 4-methoxyaniline according to the procedure of Example 5. ¹H NMR(DMSO-d₆): δ 3.78 (s, 3H); 6.95-7.1 (m, 3H); 7.3-7.45 (m, 2.5H); 7.60(d, J=8.5 Hz, 0.5H); 8.05 and 8.65 (2 d, J=12 Hz, 1H), 10.2 and 10.75 (2s, 1H); 10.95 and 11.55 (2 brd d, J=12 Hz, 1H). ES-MS: m/z 308 (M+H)⁺.

EXAMPLE 208-{(Z)-[4-(4-Morpholinyl)anilino]methylidene}-6H-[1,3]thiazolo[5,4-e]indol-7-one

Prepared according to Procedure G with 4-(4-morpholino)aniline in 78%yield. ¹H NMR (DMSO-d₆): δ 10.96 (d, 1H, J=12.6 Hz), 10.76 (s, 1H), 9.20(s, 1H), 7.95 (d, 1H, J=12.5 Hz), 7.74 (d, 1H, J=8.4Hz), 7.31 (d, 2H,J=8.8 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.99 (d, 2H, J=9.0 Hz), 3.72 (t, 4H,J=4.7 Hz), 3.07 (t, 4H, J=4.8 Hz); ES-MS m/z 379 (M+H).

EXAMPLE 21N-(4-{[(Z)-(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}phenyl)acetamide

Prepared according to Procedure G with N-(4-aminophenyl)acetamide in 87%yield. ¹H NMR (DMSO-d₆): δ 11.01 (d, 1H, J=12.5 Hz), 10.80 (s, 1H), 9.95(s, 1H), 9.22 (s, 1H), 7.99 (d, 1H, J=12.5 Hz), 7.75 (d, 1H, J=8.4 Hz),7.60(d, 2H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 7.09 (d, 1H, J=8.4 Hz),2.01 (s, 3H).

EXAMPLE 228-{(Z)-[4-(2-Hydroxyethyl)anilino]methylidene}-6H-[1,3]thiazolo[5,4-e]indol-7-one

Prepared according to Procedure G with 4-(2-hydroxyethyl)aniline in 41%yield. ¹H NMR (DMSO-d₆): δ 10.98 (d, 1H, J=12.5 Hz), 10.81 (s, 1H), 9.22(s,1H), 8.00 (d, 1H, J=12.5 Hz), 7.76 (d, 1H, J=8.4 Hz), 7.31 (d, 2H,J=8.4 Hz), 7.24 (d, 2H, J=8.4 Hz), 7.09 (d, 1H, J=8.4 Hz), 4.62 (t, 1H,J=5.1 Hz), 3.59-3.54 (m, 2H), 2.69 (t, 2H, J=7.0 Hz); ES-MS m/z 338(M+H).

EXAMPLE 238-{(Z)-[4-(4-Pyridinylmethyl)anilino]methylidene}-6H-[1,3]thiazolo[5,4-e]indol-7-one

Prepared according to Procedure G with 4-(4-pyridylmethyl)aniline in 66%yield. ¹H NMR (DMSO-d₆): δ 10.99 (d, 1H, J=12.5 Hz), 10.84 (s, 1H), 9.23(s, 1H), 8.74 (d, 2H, J=6.4 Hz), 8.00 (d, 1H, J=12.3 Hz), 7.82 (d, 2H,J=6.2Hz), 7.77 (d,1H, J=8.4 Hz), 7.40 (d,2H, J=8.6 Hz), 7.35 (d, 2H,J=8.4 Hz) 7.09 (s,1H), 4.20 (s, 2H); ES-MS m/z 384 (M+H).

EXAMPLE 244-{[(Z)-(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzamide

Prepared according to Procedure G with 4-aminobenzamide in 73% yield. ¹HNMR (DMSO-d₆): δ 11.14 (d, 1H, J=12.3 Hz), 10.90 (s, 1H), 9.27 (s, 1H),8.10 (d,1H, J=12.3 Hz), 7.93 (d, 3H, J=8.4 Hz), 7.82 (d, 1H, J=8.4 Hz),7.49 (d, 2H, J=8.6 Hz), 7.30 (s, 1H), 7.12 (d, 1H, J=8.4 Hz); ES-MS m/z337 (M+H).

EXAMPLE 25 6-Bromo-3{(Z andE)-[4-(4-morpholinyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared according to Example 1 in 87% yield to give ˜4:1 isomermixture. Principal isomer: ¹H NMR (DMSO-d₆): δ 10.67 (d, 1H, J=12.5 Hz),10.56(s,1H), 8.57 (d,1H, J=12.8 Hz), 7.48 (d,1H, J=7.9 Hz), 7.35-7.29(m,2H), 7.11-7.04 (m, 3H), 6.93 (s,1H), 3.76 (s, 4H), 3.15 (s,4H); ES-MSm/z 400, 402 (M+1).

EXAMPLE 264-{[(Z)-(6-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzamide

Prepared according to Example 1 with 4-aminobenzamide in 70% yield. ¹HNMR (DMSO-d₆): δ 10.75 (d,1H, J=12.5 Hz), 10.65 (s,1H), 8.69 (d,1H,J=12.5 Hz), 7.87 (d,3H, J=8.6 Hz), 7.54 (d,1H, J=7.9Hz), 7.44 (d, 2H,J=8.6 Hz), 7.24 (s,1H), 7.09 (d,1H, J=8.2 Hz), 6.95 (d,1H, J=1.4 Hz);ES-MS m/z356,358 (M−1).

EXAMPLE 27 N-(4-{[(Z andE)-(6-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)acetamide

Prepared according to Example 1 with N-(4-aminophenyl)acetamide in 79%yield to give ˜9:1 isomer mixture. Principal isomer: ¹H NMR (DMSO-d₆): δ10.75 (d,1H, J=12.5 Hz), 10.65 (s,1H), 8.69 (d,1H, J=12.5 Hz), 7.87(d,3H, J=8.6 Hz), 7.54 (d,1H, J=7.9 Hz), 7.44 (d,2H, J=8.6 Hz), 7.24(s,1H), 7.09 (d,1H, J=8.2 Hz), 6.95 (d,1H, J=1.4 Hz); ES-MS m/z 370, 372(M−1).

EXAMPLE 286-Bromo-3-{(Z)-[4-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared according to Example 1 with 4-(2-hydroxyethyl)aniline in 85%yield. ¹H NMR (DMSO-d₆): δ 10.67 (d,1H, J=12.8 Hz), 10.58 (s, 1H), 8.61(d,1H, J=12.6 Hz), 7.50 (d,1H, J=8.2 Hz), 7.29 (d,2H, J=8.4 Hz), 7.19(d,2H, J=8.2 Hz), 7.06 (d,1H, J=8.1 Hz ), 6.93 (d,1H, J=1.5 Hz), 4.60(t, 1H,J=5.1 Hz), 3.55 (m,2H), 2.66 (t,2H, J=7.0 Hz); MS-ES m/z 357, 359(M−1).

EXAMPLE 291-{(Z)-[4-(4-Morpholinyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-(4-morpholino)aniline in 65%yield. ¹H NMR (DMSO-d₆): δ 11.77 (d,1H, J=12.3 Hz), 10.88 (s,1H), 8.77(m,2H), 8.69 (d,1H, J=4.0 Hz), 7.67 (d, 1H, J=8.6 Hz), 7.5-7.4 (m, 4H),6.98 (d,2H, J=8.8 Hz), 3.72 (t,4H, J=4.5 Hz), 3.07 (t, 4H, J=4.6 Hz);ES-MS m/z 373 (M+H).

EXAMPLE 301-{(Z)-[4-(4-Pyridinylmethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-(4-pyridylmethyl)aniline in 59%yield. ¹H NMR (DMSO-d₆): δ 11.74 (d,1H, J=12.1 Hz), 10.93 (s,1H),8.80-8.75 (m,2H), 8.70 (d,1H, J=3.9 Hz), 8.44 (d,2H, J=5.3 Hz), 7.70 (d,1H, J=8.6 Hz), 7.47-7.43 (m,3H), 7.39 (d,1H, J=8.8 Hz), 7.28 (d,2H,J=8.1 Hz), 7.24 (d,2H, J=5.1 Hz), 3.95 (s,2H); ES-MS m/z 379 (M+H).

EXAMPLE 31N-(4-{[(Z)-(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}phenyl)acetamide

Prepared according to Example 13 with N-(4-aminophenyl)acetamide in 72%yield. ¹H NMR (DMSO-d₆): δ 11.77 (d,1H, J=12.1 Hz), 10.92 (s, 1H), 9.95(s,1H), 8.8-8.77 (m,2H), 8.70 (d,1H, J=3.5 Hz), 7.69 (d,1H, J=8.8 Hz),7.60 (d,2H, J=9.0 Hz), 7.5-7.43 (m,3H), 7.39 (d,1H, J=8.6 Hz), 2.01(s,3H) ES-MS m/z 345 (M+H).

EXAMPLE 321-{(Z)-[4-(2-Hydroxyethyl)anilino]methylidene}-(1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-(2-hydroxyethyl)aniline in 75%yield. ¹H NMR (DMSO-d₆): δ 11.75 (d,1H, J=12.1 Hz), 10.92 (s, 1H),8.82-8.79 (m,2H), 8.70 (d,1H, J=3.9 Hz), 7.70 (d,1H, J=8.6 Hz), 7.5-7.4(m 4H), 7.23 (d,2H, J=8.2 Hz), 4.62 (t,1H, J=5.1 Hz), 3.6-3.55 (m,2H),2.70 (t,2H, J=7.0 Hz); ES-MS m/z 332 (M+H).

EXAMPLE 334-{[(Z)-(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzamide

Prepared according to Example 13 with 4-aminobenzamide in 54% yield. ¹HNMR (DMSO-d₆): δ 11.90 (d,1H, J=11.9 Hz), 11.03 (s, 1H), 8.87-8.83(m,2H), 8.76 (d,1H, J=4.0 Hz), 7.93-7.89 (m,3H), 7.78 (d,1H,J=8.8 Hz),7.61 (d,2H, J=8.6 Hz), 7.52 (dd,1H, J=4.1,8.5 Hz), 7.45 (d,1H,J=8.8 Hz),7.3 (s, 1H); ES-MS m/z 331 (M+H).

EXAMPLE 341-[(Z)-(4-Hydroxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-hydroxyaniline in 84% yield. ¹HNMR (DMSO-d₆): δ 11.76 (d,1H, J=12.3 Hz), 10.90 (s, 1H), 9.44 (s, 1H),8.77-8.68 (m,3H), 7.71 (d, 1H,J=8.8 Hz), 7.44-7.33 (m,4H), 6.83 (d,2H,J=8.6 Hz); ES-MS m/z 304 (M+H).

EXAMPLE 356-(2-Furyl)-3-{(Z)-[4-(4-morpholinyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared from the dimethylaminomethylene derivative (Procedure E) of6-(2-furyl)oxindole (prepared according to Procedure I) with4-(4-morpholino)aniline according to Procedure G in 90% yield. ¹H NMR(DMSO-d₆): δ 10.66 (d,1H, J=12.6 Hz), 10.51 (s,1H), 8.51 (d, 1H, J=12.8Hz), 7.65 (s,1H), 7.56 (d,1H, J=7.9 Hz), 7.29-7.25 (m,3H), 7.1 (s,1H),6.95 (d,2H, J=8.8 Hz), 6.77 (d,1H, J=2.9 Hz), 6.52 (s,1H), 3.71 (s,4H),3.05 (s,4H); ES-MS m/z 388 (M+H).

EXAMPLE 36 N-[4-({(Z andE)-[6-(2-Furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)phenyl]acetamide

Prepared according to Example 35 with N-(4-aminophenyl)acetamide in 29%yield. ¹H NMR (DMSO-d₆): δ 10.68 (d,1H, J=12.6 Hz), 10.55 (s,1H), 9.91(s,1H), 8.53 (d,1H, J=12.6 Hz), 7.66 (s,1H), 7.57 -7.54 (m,3H),7.32-7.27 (m,3H), 7.10 (s,1H), 6.78 (d,1H, J=2.9 Hz), 6.53 (s,1H), 2.00(s,3H); ES-MS m/z 358 (M−H).

EXAMPLE 376-(2-Furyl)-3-{(Z)-[4-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2one

Prepared according to Example 35 with 4-(2-hydroxyethyl)aniline in 63%yield. ¹H NMR (DMSO-d₆): δ 10.68 (d,1H, J=12.5 Hz), 10.56 (s,1H), 8.57(d,1H, J=12.6 Hz), 7.66 (s,1H), 7.58 (d,1H, J=7.9 Hz), 7.28 (br s,3H),7.19 (d,2H, J=8.1 Hz), 7.11 (s,1H), 6.78 (s,1H), 6.53 (s,1H), 4.61(t,1H, J=4.9 Hz), 3.58 -3.55 (m, 2H), 2.67 (t, 2H, J=6.9 Hz); ES-MS m/z345 (M−H).

EXAMPLE 383-{(Z)-[4-(4-Morpholinyl)anilino]methylidene}-6-vinyl-1,3-dihydro-2H-indol-2-one

Prepared according to Procedure G with the dimethylaminomethylenederivative (Procedure E) of 6-vinyloxindole (Procedure I) and4-(4-morpholino)aniline in 75% yield. ¹H NMR (DMSO-d₆): δ 10.65 (d,1H,J=2.8 Hz), 10.43 (s,1H), 8.48 (d,1H, J=12.5 Hz), 7.48 (d,1H, J=7.9 Hz),7.27 (d,2H, J=8.9 Hz), 7.00 (d,1H, J=7.9 Hz), 6.95 (d,2H, J=8.9 Hz),6.89 (s,1H), 6.87-6.62 (m,1H), 5.64 (d,1H, J=17.84 Hz), 5.08 (d,1H,J=11.1 Hz), 3.71 (t,4H, J=4.6 Hz), 3,05 (t,4H, J=4.6 Hz); ES-MS m/z 346(M−H).

EXAMPLE 393-{(Z)-[4-(4-Pyridinylmethyl)anilino]methylidene}-vinyl-1,3-dihydro-2H-indol-2-one

Prepared according to Example 38 with 4-(4-pyridylmethyl)aniline in 51%yield. ¹H NMR (DMSO-d₆): δ 10.66 (d,1H, J=12.5 Hz), 10.49 (s,1H), 8,53(d,1H, J=12.5 Hz), 8.43 (d,2H, J=5 Hz), 7.50 (d,1H, J=7.9 Hz), 7.32(d,2H, J=8.6 Hz), 7.24-7.21 (m,4H), 7.01 (d,1H, J=7.9 Hz), 6,89 (s,1H),6.70-6.63 (m,1H), 5.65 (d,1H, J=17.5 Hz), 5.10 (d,1H, J=11.1 Hz), 3.91(s,2H); ES-MS m/z 352 (M−H).

EXAMPLE 40N-(4-{(Z)-[(2Oxo-6-vinyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)acetamide

Prepared according to Example 38 with N-(4-aminophenyl)acetamide in 42%yield. ¹H NMR (DMSO-d₆): δ 10.67 (d,1H, J=12.5 Hz), 10.47 (s,1H), 9.90(s,1H), 8.50 (d,1H, J=12.5 Hz), 7.55 (d,2H, J=8.6 Hz), 7.49 (d,1H,J=7.85 Hz), 7.30 (d,2H, J=8.9 Hz), 7.01 (d,1H, J=7.9 Hz), 6.89 (s,1H),6.70-6.63 (m,1H), 5.65 (d,1H, J=17.5 Hz), 5.09 (d,1H, J=11.1 Hz), 2.00(s,3H); ES-MS m/z 318 (M−H).

EXAMPLE 413-{(Z)-[4-(2-Hydroxyethyl)anilino]methylidene}-6-vinyl-1,3-dihydro-2H-indol-2-one

Prepared according to Example 38 with 4-(2-hydroxyethyl)aniline in 55%yield. ¹H NMR (DMSO-d₆): δ 10.66 (d,1H,J=12.5 Hz), 10.48 (s,1H), 8.54(d,1H, J=12.5 Hz), 7.51 (d,1H, J=7.9 Hz), 7.28 (d,2H, J=8.2 Hz), 7.19(d,2H, J=8.2 Hz), 7.01 (d,1H, J=7.9 Hz), 6.9 (s,1H), 6.88-6.63 (m,1H),5.65 (d,1H, J=17.5 Hz), 5.09 (d,1H, J=11.1 Hz), 4.60 (t,1H, J=5.0 Hz),3.58-3.53 (m,2H), 2.66 (t,2H, J=7.0 Hz); ES-MS m/z 305 (M−H).

EXAMPLE 426-(2-Furyl)-3-{(Z)-[4(4-pyridinylmethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared according to Example 35 with 4-(4-pyridylmethyl)aniline in 42%yield. ¹H NMR (DMSO-d₆): δ 10.67 (d,1H, J=112.6 Hz), 10.56 (s,1H), 8.56(d,1H, J=12.6 Hz), 8.43 (d,2H, J=5.3 Hz), 7.66 (s,1H), 7.57 (d,1H, J=8.1Hz), 7.34-7.22 (m,7H), 7.10 (s,1H), 6.79 (d,1H, J=3.3 Hz), 6.53 (s, 1H),3.91 (s,2H); ES-MS m/z 391 (M−H).

EXAMPLE 436-(2-Furyl)-3-[(Z)-(4-hydroxyanilino)methylidene]-1,3-dihydro-2H-indol-2-one

Prepared according to Example 35 with 4-hydroxyaniline in 44% yield. ¹HNMR (DMSO-d₆): δ 10.63 (d,1H, J=12.8 Hz), 10.49 (s,1H), 9.32 (s,1H),8.46 (d,1H, J=12.8 Hz), 7.65 (s,1H), 7.54 (d,1H, J=7.9 Hz), 7.26 (d,1H,J=7.9 Hz), 7.21 (d,2H, J=8.8 Hz), 7.01 (s,1H), 6.77-6.74 (m,3H), 6.52(s,1H); ES-MS m/z 317 (M−H).

EXAMPLE 443-{(Z)-[4-(4-Morpholinyl)anilino]methylidene}-6-(2-thienyl)-1,3-dihydro-2H-indol-2-one

Prepared from the dimethylaminomethylene derivative (Procedure E) of6-(2-thienyl)oxindole (prepared according to Procedure I) with4-(4-morpholino)aniline according to Procedure G in 47% yield. ¹H NMR(DMSO-d₆): δ 10.67 (d,1H, J=12.9 Hz), 10.65 (s,1H), 8.52 (d,1H, J=12.8Hz), 7.55 (d,1H, J=7.9 Hz), 7.42 (d,1H,J=5.1 Hz), 7.36 (d,1H, J=3.3 Hz)7.29 (2H, 8.8 Hz),7.22 (d,1H, J=7.9 Hz), 7.08-7.07 (m,1H), 7.04 (s,1H),6.95 (d,2H, J=9.0 Hz), 3.71 (t,4H, J=4.5 Hz), 3.05 (t,4H, J=4.6 Hz).

EXAMPLE 45N-[4-({(Z)-[2-Oxo-6-(2-thienyl)-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)phenyl]acetamide

Prepared according to Example 44 with N-(4-aminophenyl)acetamide in 33%yield. ¹H NMR (DMSO-d₆): δ 10.68 (d,1H, J=12.6 Hz), 10.52 (s,1H), 9.91(s,1H), 8.53 (d,1H, J=12.6 Hz), 7.55 (d,3H, J=8.4 Hz), 7.43 (d,1H, J=5.1Hz), 7.37 (d,1H, J=3.1 Hz), 7.32 (d,2H, J=8.8 Hz), 7.23 (d,1H, J=9.2Hz), 7.07 (t,1H, J=4.3 Hz), 7.04 (s,1H), 2.00 (s,3H); ES-MS m/z 374(M−H).

EXAMPLE 466-Bromo-3-{(Z)-[3-(hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared according to Example 1 with 3-(hydroxymethyl)aniline in 54%yield. ¹H NMR (DMSO-d₆): δ 10.74 (d,1H, J=12.8 Hz), 10.60 (s,1H), 8.67(d,1H, J=12.8 Hz), 7.53 (d,1H, J=8.2 Hz), 7.30 (d,2H, J=7.3 Hz), 7.24(d,1H, J=8.2 Hz), 7.07 (d,1H, J=9.3 Hz), 7.02 (d,1H, 7.3 Hz), 6.94(s,1H), 5.23 (t,1H, J=5.7 Hz), 4.48 (d,2H, J=5.7 Hz); ES-MS m/z 343, 345(M−1).

EXAMPLE 47 6-Bromo-3-{(Z andE)-[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one

Prepared according to Example 1 with2-(4-aminophenyl)-3-methyl-pyrazoline-5-one in 45% yield as ˜9:1 isomermixture. Major isomer: ¹H NMR (DMSO-d₆): δ 10.73 (d,1H, J=12.6 Hz),10.60(s,1H), 9.82 (s,1H), 8.65 (d,1H, J=12.6 Hz), 7.52 (d,1H, J=8.1 Hz),7.47 (d,2H, J=8.8 Hz), 7.42 (d,2H, J=8.8 Hz), 7.08 (d,1H, J=8.1 Hz),6.94 (s,1H), 5.54 (s, 1H), 2.23 (s,3H); ES-MS m/z 411, 413 (M+1).

EXAMPLE 483-Ethyl-3-(4-{(Z)-[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}phenyl)-2,6-piperidinedione

A mixture of8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one(Procedure E, 0.040 g, 0.163 mmol), DL-aminoglutethimide (0.055 g, 0.237mmol) in absolute ethanol (5 ml) was heated with stirring at 90° C. for16 h. The reaction was diluted with ethanol and diethyl ether and theproduct collected by filtration to yield 0.038 g (54%) of the titlecompound. ¹H NMR (DMSO-d₆): δ 11.00 (d,1H, J=12.5 Hz), 10.88 (s,1H),10.83 (s,1H), 9.23 (s, H), 8.02 (d,1H, J=12.5 Hz), 7.77 (d,1H, J=8. 6Hz), 7.42 (d,2H, J=8.9 Hz), 7.31 (d,2H, J=8.9 Hz), 7.09 (d,1H, J=8.2Hz), 2.44-2.34 (m,2H), 2.15-2.13 (m,2H), 1.86-1.02 (m,2H), 0.75 (t,3H,J=7.3 Hz); ES-MS m/z 431 (M−H).

EXAMPLE 498-[(Z)-(4-Phenoxyanilino)methylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one

Prepared according to Procedure G with 4-phenoxyaniline in 86% yield. ¹HNMR (DMSO-d₆): δ 11.02 (d,1H, J=12.5 Hz), 10.81 (s,1H), 9.22 (s,1H),7.99 (d,1H, J=12.3 Hz), 7.76 (d,1H, J=8.42 Hz), 7.46 (d,2H, J=9.0 Hz)7.37 (t,2H, J=7.9 Hz), 7.12-7.06 (m,4H), 6.98 (d,2H, J=8.1 Hz); ES-MSm/z 384 (M−H).

EXAMPLE 508{(Z)-[4-(Benzyloxy)anilino]methylidene}-6H-[1,3]thiazolo[5,4e]indol-7-one

Prepared according to Procedure G with 4-(benzyloxy)aniline in 90%yield. ¹H NMR (DMSO-d₆): δ 10.96 (d,1H, J=12.5 Hz), 10.77 (s,1H), 9.21(s,1H), 7.95 (d,1H, J=12.5 Hz), 7.74 (d,1H, J=8.4 Hz), 7.43 (d,2H, J=7.1Hz), 7.39-7.35 (m,4H), 7.32-7.30 (m,1H), 7.09-7.04 (m,3H), 5.09 (s,2H);ES-MS m/z 398 (M−H).

EXAMPLE 51 Methyl4-(4-{[((Z)-7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}phenoxy)benzoate

Prepared according to Procedure G with methyl 4-(4-aminophenoxy)benzoatein 35% yield. ¹H NMR (DMSO-d₆): δ 11.05 (d,1H, J=12.3 Hz), 10.83 (s,1H),9.22 (s,1H), 8.01 (d,1H, 12.3 Hz), 7.95-7.93 (m,2H), 7.77 (d,1H, J=8.4Hz), 7.52 (d,2H, J=9.0 Hz), 7.19 (d,2H, J=8.8 Hz), 7.10 (d,1H, J=8.4Hz), 7.03 (d,2H, J=8.8 Hz), 3.80 (s,3H); ES-MS m/z 442 (M−H).

EXAMPLE 52 Methyl3-(4-{(Z)-[(7-oxo-4,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}phenoxy)benzoate

Prepared according to Procedure G with methyl 3-(4-aminophenoxy)benzoatein 71% yield. ¹H NMR (DMSO-d₆): δ 11.05 (d,1H, J=12.5 Hz), 10.82 (s,1H),9.22 (s,1H), 8.01 (d,1H, J=12.3 Hz), 7.77(d,1H, J=8.4 Hz), 7.68 (d,1H,J=7.9 Hz), 7.55-7.49 (m,3H), 7.41 (s,1H), 7.31 (dd,1H, J=2.3,8.2 Hz),7.14 (d,2H, J=8.8 Hz), 7.09 (d,1H, J=8.4 Hz), 3.08 (s,3H); ES-MS m/z 442(M−H).

EXAMPLE 538-{(Z)-[3-(Hydroxymethyl)anilino]methylidene}-6H-[1,3]thiazolo[5,4-e]indol-7-one

Prepared according to Procedure G with 3-(hydroxymethyl)aniline in 83%yield. ¹H NMR (DMSO-d₆): δ 11.05 (d,1H, J=12. 5 Hz), 10.84 (s,1H), 9.23(s,1H), 8.05 (d,1H, 12.3 Hz), 7.77 (d, 1H, J=8.4 Hz), 7.37-7.26 (m,3H),7.10 (d,1H, J=8.4 Hz), 7.06 (d,1H, J=7.5 Hz), 5.27 (t,1H,J=5.7 Hz), 4.52(d,2H, J=5.9 Hz); ES-MS m/z 322 (M−H).

EXAMPLE 543-{(Z)-[(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzamide

Prepared according to Procedure G with 3-aminobenzamide in 84% yield. ¹HNMR (DMSO-d₆): δ 11.13 (d,1H, J=12.3 Hz), 10.87 (s,1H), 9.23 (s,1H),8.12-8.07 (m,2H), 7.84 (s,1H), 7.78 (d,1H, J=8.4 Hz), 7.58 (t,2H, J=7.7Hz), 7.47 (t,2H, J=7.8 Hz), 7.10 (d,1H, J=8.4 Hz); ES-MS m/z 335 (M−H).

EXAMPLE 558-{(Z)-[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-6H-[1,3]thiazolo[5,4-e]indol-7-one

A mixture of8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one(Procedure E, 0.040 g, 0.163 mmol),2-(4-aminophenyl)-3-methyl-pyrazoline-5-one (0.047 g, 0.248 mmol) inabsolute ethanol (5 ml) was heated with stirring at 90° C. for 16 h. Thereaction was diluted with ethanol and diethyl ether and the productcollected by filtration to yield 0.052 (83%) of the title compound. ¹HNMR (DMSO-d₆): δ 11.08 (d,1H, J=12.3 Hz), 10.84 (s,1H), 9.85 (s,1H),9.23 (s,1H), 8.05 (d,1H, J=12.1 Hz), 7.78 (d,1H, J=8.2 Hz), 7.51-7.45(m,4H), 7.10 (d,1H, J=8.4Hz), 5.55 (s,1H), 2.25 (s,3H); ES-MS m/z 388(M−H).

EXAMPLE 56 Methyl4-{(Z)-[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzoate

Prepared according to Procedure G methyl 4-aminobenzoate in 47% yield.¹H NMR (DMSO-d₆): δ 11.17 (d,1H, J=12.1 Hz), 10.91 (s,1H), 9.25 (s,1H),8.07 (d,1H, 12.1 Hz), 7.95 (d,2H, J=8.6 Hz), 7.81 (d,1H, J=8.2 Hz),7.51(d,2H, J=8.6 Hz), 7.10 (d,1H, J=8.4 Hz), 3.81 (s,3H);ES-MS m/z 350(M−H).

EXAMPLE 574-{(Z)-[(7-Oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}benzonitrile

Prepared according to Procedure G with 4-aminobenzonitrile in 71% yield.¹H NMR (DMSO-d₆): δ 11.14 (d,1H, J=11.9 Hz), 10.92 (s,1H), 9.25 (s,1H),8.04 (d,1H, J=11.9 Hz), 7.82 (dd,3H, J=2.4, 8.7 Hz), 7.59 (d,2H, J=8.8Hz), 7.10 (d,1 H, J=8.4 Hz); ES-MS m/z 317 (M−H).

EXAMPLE 58N-Methyl-N-(4-{(Z)-[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}phenyl)acetamide

A mixture of8-dimethylamino-methylene-6,8dihydro-1-thia-3,6-diaza-as-indacen-7-one(Procedure E, 0.040 g, 0.163 mmol), 4-amino-N-methylacetanilide (0.040g, 0.244 mmol) in absolute ethanol (5 ml) was heated with stirring at90° C. for 16 h. The reaction was diluted with ethanol and diethyl etherand the product collected by filtration to yield 0.038 g (64%) of thetitle compound. ¹H NMR (DMSO-d₆): δ 11.03 (d,1 H, J=12.3 Hz), 10.84(s,1H), 9.23 (s,1H), 8.02 (d,1H, J=12.3 Hz), 7.78 (d,1H, J=8.4 Hz), 7.48(d,2H, J=8.2 Hz), 7.35 (d,2H, J=8.2 Hz), 7.09 (d,1H, J=8.4 Hz), 3.11(s,3H), 1.76 (s, 3H); ES-MS m/z 363 (M−H).

EXAMPLE 591-[(Z)-(4-Phenoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-phenoxyaniline in 79% yield. ¹HNMR (DMSO-d₆): δ 11.78 (d,1H, J=12.1 Hz), 10.93 (s,1H), 8.81-8.78 (m2H),8.70 (d,1H, J=4.0 Hz), 7.70 (d,1H, J=8.6 Hz), 7.56 (d,2H, J=8.8 Hz),7.45 (dd,1H, J=4.1, 8.5 Hz), 7.41-7.35 (m, 3H), 7.12-7.05 (m, 3H), 6.98(d,2H, J=8.2 Hz); ES-MS m/z 378 (M−H).

Example 601-{(Z)-[4-(Benzyloxy)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-(benzyloxy)aniline in 59% yield.¹H NMR (DMSO-d₆): δ 11.80 (d,1H, J=12.3 Hz), 10.99 (s,1H), 8.95 (d,1H,J=8.1 Hz), 8.82-8.77 (m,2H), 7.73 (d,1H, J=8.8 Hz), 7.54 (dd,1H,J=4.1,8.3 Hz), 7.49-7.30 (m,8H), 7.05 (d,2H, J=9.0 Hz), 5.11 (s,2H),ES-MS m/z 394 (M+H).

EXAMPLE 61 Methyl4-(4{(Z)-[(2-oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-4-ylidene)methyl]amino}phenoxy)benzoate

Prepared according to Example 13 with methyl 4-(4-aminophenoxy)benzoatein 69% yield. ¹H NMR (DMSO-d₆): δ 11.80 (d,1H, J=12.1 Hz), 10.94 (s,1H),8.83-8.80 (m,2H), 8.70 (d,1H, J=3.9 Hz), 7.95 (d,2H, J=8.8 Hz), 7.71(d,1H, J=8.8 Hz), 7.62 (d,2H, J=9.0 Hz), 7.45 (dd,1H, J=4.1, 8.5 Hz),7.41 (d, 1H, J=8.8 Hz), 7.18 (d,2H, J=8.8 Hz), 7.03 (d,2H, J=8.8 Hz),3.80 (s,3H); ES-MS m/z 436 (M−H).

EXAMPLE 62 Methyl3-(4{(Z)-[(2-oxo-2,3dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}phenoxy)benzoate

Prepared according to Example 13 with methyl 3-(4-aminophenoxy)benzoatein 45% yield. ¹H NMR (DMSO-d₆): δ 11.96 (d,1H, J=12.1 Hz), 11.33 (s,1H),9.44 (d,1H, J=8.2 Hz), 9.01-8.98 (m,2H), 7.95 (d,1H, J=8.8 Hz), 7.85(dd,1H, J=4.9, 8.4 Hz), 7.72-7.66 (m,4H), 7.54 (t,1H, J=8.0 Hz), 7.42(s,1H), 7.33 (d,1H, J=8.2 Hz), 7.17 (d,2H, J=8.6 Hz), 3.80 (s,3H); ES-MSm/z 438 (M+H).

EXAMPLE 633-Ethyl-3-(4-{(Z)-[(2-oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}phenyl)-2,6-piperidinedione

Prepared according to Example 13 with DL-aminoglutethimide in 81% yield.¹H NMR (DMSO-d₆): δ 11.72 (d,1H, J=11.7 Hz), 10.93 (s,1H), 10.88 (s,1H),8.82-8.77 (m,2H), 8.70 (d,1H, J=2.9 Hz), 7.71 (d,1H, J=8.8 Hz), 7.52(d,2H, J=8.8 Hz), 7.45 (dd,1H, J=4.1,8.5 Hz), 7.40 (d, 1H, J=8.8 Hz),7.30 (d,2H, J=8.6 Hz), 2.36-2.16 (m,2H), 2.15-2.12 (m,2H), 1.90-1.77(m,2H 0.76 (t,3H, J=7.3 Hz); ES-MS m/z 425 (M−H).

EXAMPLE 641-[(Z)-(4-Benzoylanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 4-benzoylaniline in 76% yield. ¹HNMR (DMSO-d₆): δ 11.92 (d,1H, J=11.7 Hz), 11.04 (s,1H), 8.88 (d,1H,J=11.7 Hz), 8.84 (d,1H, J=8.6 Hz), 8.73 (d,1H, J=3.1 Hz), 7.80-7.53(m,10H), 7.49 (dd,1H, J=4.1, 8.5 Hz), 7.42 (d,1H, J=8.8 Hz); ES-MS m/z390 (M−H).

Example 651-{(Z)-[3-(Hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 3-(hydroxymethyl)aniline in 78%yield. ¹H NMR (DMSO-d₆): δ 11.84 (d,1H, J=12.1 Hz), 10.36 (s,1H),8.86-8.80 (m,2H), 8.72 (d,1H, J=4.0 Hz), 7.72 (d,1H, J=8.7 Hz), 7.48(dd,1H, J=4.1,8.5 Hz), 7.43-7.33 (m,4H), 7.07 (d,1H, J=7.5 Hz), 5.25(s,1H), 4.53 (dd,2H, J=4.5 Hz); ES-MS m/z 316 (M−H).

EXAMPLE 661-{(Z)-[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1H-pyrrolo[3,2-f]quinolin-2(3H)-one

Prepared according to Example 13 with2-(4-aminophenyl)-3-methyl-pyrazoline-5-one in 69% yield. ¹H NMR(DMSO-d₆): δ 11.83 (d,1H, J=11.9 Hz), 10.05 (s,1H), 9.84 (s,1H),8.86-8.82 (m,2H), 8.71 (d,₁H, J=2.9 Hz), 7.72 (d,1H, J=8.8 Hz), 7.60(d,2H, J=8.8 Hz), 7.48-7.44 (m,3H), 7.41 (d,1H, J=8.8 Hz), 5.55 (s,1H),2.25 (s,3H); ES-MS m/z 382 (M−H).

EXAMPLE 671-((E)-{4-[(E)-2-(4-Hydroxyphenyl)ethenyl]anilino}-methylidene)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Prepared according to Example 13 with 2-(4-hydroxyphenyl)ethenyl]anilinein 90% yield. ¹H NMR (DMSO-d₆): δ 11.86 (d,1H, J=11.9 Hz), 10.95 (s,1H),9.53 (s,1H), 8.86-8.83 (m,2H), 8.71 (d,1H, J=3.3 Hz), 7.71 (d,1H, J=8.6Hz), 7.58-7.45 (m,5H), 7.42-7.38 (m,3H), 7.12-6.98 (m,2H), 6.74 (d,2H,J=8.6 Hz); ES-MS m/z 404 (M−H).

Example 683{(Z)-[(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzamide

Prepared according to Example 13 with 3-aminobenzamide in 66% yield. ¹HNMR (DMSO-d₆): δ 11.86 (d,1H, J=11.9 Hz), 10.98 (s,1H), 8.89-8.80(m,2H), 8.72 (d,1H, J=2.9 Hz), 8.06 (s,1H), 7.88 (s,1H) 7.74-7.69(m,2H), 7.59 (d,1H, J=7.7 Hz), 7.51-7.45 (m,3H), 7.41 (d,1H, J=8.8 Hz);ES-MS m/z 329 (M−H).

EXAMPLE 694-{(Z)-[(2-Oxo-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzonitrile

Prepared according to Example 13 with 4-aminobenzonitrile in 82% yield.¹H NMR (DMSO-d₆): δ 11.84 (d,1H, J=11.7 Hz), 11.03 (s,1H), 8.84-8.73(m,2H), 8.72 (dd,1H, J=1.2,4.1 Hz), 7.82 (d, 2H, J=8.6 Hz), 7.76 (d,1H,J=8.8 Hz), 7.69 (d,2H, J=8.8 Hz), 7.48 (dd,1H, J=4.1,8.5 Hz), 7.41(d,1H, J=8.6 Hz); ES-MS m/z 311 (M−H).

EXAMPLE 70 Methyl4-{(Z)-[(2-oxo-2,3dihydro-1H-pyrrolo[3,2-f]quinolin-1-ylidene)methyl]amino}benzoate

Prepared according to Example 13 with methyl 4-aminobenzoate in 44%yield. ¹H NMR (DMSO-d₆): δ 11.91 (d,1H, J=11.8 Hz), 11.03 (s,1H),8.88-8.83 (m,2H), 8.72 (dd,1H,J=1.3,4.1 Hz), 7.95 (d,2H, J=8.6 Hz), 7.75(d,1H, J=8.9 Hz), 7.63 (d,2H, J=8.6 Hz), 7.49 (dd,1H, J=3.9,8.6 Hz),7.41 (d,1H, J=8.6 Hz), 3.82 (s,3H); ES-MS m/z 344 (M−H).

Example 718-[(Z)-(4-{[2-(Diethylamino)ethyl]sulfonyl}anilino)methylidene]-6H-[1,3]thiazolo[5,4-e]indol-7one

Prepared according to Procedure G with4-[2-(diethylamino)ethylsulfonyl]aniline in 18% yield. ¹H NMR (DMSO-d₆):δ 11.20 (d,1H, J=11.9 Hz), 10.93 (s,1H), 9.26 (s1H), 8.08 (d,1H, J=11.9Hz), 7.87 (d,2H, J=8.6 Hz), 7.82 (d,1H, J=8.42 Hz), 7.63 (d,2H, J=8.6Hz), 7.11 (d,1H, J=8.24Hz), 3.46-3.38 (m,2H), 2.8-2.7 (m,2H), 2.3-2.2(m,4H), 0.80 (t,6H, J=7.0 Hz); ES-MS m/z 455 (M−H).

EXAMPLE 721-[(Z)-(4-{[2-(Diethylamino)ethyl]sulfonyl}anilino)methylidene]-1H-pyrrolo[3,2-f]quinolin-2(3H)-one

Prepared according to Example 13 with4-[2-(diethylamino)ethylsulfonyl]aniline in 64% yield. ¹H NMR (DMSO-d₆):δ 11.91 (d,1H, J=11.5 Hz), 11.04 (s,1H), 8.88-8.84 (m,2H), 8.73 (d, 1H,J=3.3 Hz), 7.87 (d,2H, J=8.6 Hz), 7.78-7.72 (m, 3H), 7.50 (dd,1H,J=4.1,8.5 Hz), 7.41 (d,1H, J=8.6 Hz), 3.45-3.38 (m,2H), 2.71-2.67(m,2H), 2.32 (q,4H, J=7.0 Hz), 0.80 (t,6H, J=7.1 Hz); ES-MS m/z449(M−H).

EXAMPLES 73-88 Are Described in Procedure J (vide infra) EXAMPLE 893,6-Dihydro[1,2,3]triazolo[4,5e]indole-7,8-dione8-[N-(4-methoxyphenyl)hydrazone]

See Procedure H.

EXAMPLE 90 3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-{N-4-(1,3-oxazol-5-yl)phenyl]hydrazone}

Prepared according to Procedure H with4-(1,3-oxazol-5-yl)phenylhydrazine hydrochloride in 61% yield as ˜2:1mixture of geometric isomers. ¹H NMR (DMSO-d₆): δ 7.09 and 7.26 (2 d,1:2 ratio, J=8.6 Hz, 1H); 7.55 and 7.85 (ABq, J=8.7 Hz, 4H); 7.65 (s,1H); 7.85 and 7.98 (2 d, 2:1 ratio, partially obscured by ABq, J=8.6 Hz,1H); 8.45 (s, 1H); 10.87 and 11.33 (2 s, ˜2:1 ratio, 1H). 12.95 (brd,1H). APCI-MS m/z 344 (M−H)⁻.

Example 91 3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-[N-(4-methylphenyl)hydrazone]

Prepared according to Procedure H with 4-methylphenylhydrazinehydrochloride in 18% yield as ˜1:1 mixture of E and Z isomers. ¹H NMR(DMSO-d₆): δ 2.28 (s, 3H); 7.19 (d, J=8.4 Hz, 0.5H); 7.15-7.35 (m,3.5H); 7.62 (d, J=8.4 Hz, 1H); 7.76 (d, J=8.4 Hz, 0.5H); 7.93 (d, J=8.4Hz, 0.5H); 10.7 (s, 0.5H); 11.2 (s, 1H); 12.3 and 12.35 2 s, 1H).APCI-MS m/z 291 (M−H)⁻.

Example 92 3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-(N-{4-[(E)-2-(2-pyridinyl)ethenyl]phenyl}hydrazone)

Prepared according to Procedure H with 4′-hydrazino-2-stilbazoledihydrochloride (TCl, Inc.) in 89% yield as ˜1:1 mixture of E and Zisomers as the hydrochloride salt. ¹H NMR (DMSO-d₆): δ 7.10 and 7.26 (2d, J=8.6 Hz, 1H); 7.37 and 7.41 (2 d, J=16 Hz, 1H); 7.55 (d, J=8.6 Hz,1H); 7.68 (m, 1H); 7.74-7.9 (m, 3.5H); 7.99 (d, J=16 Hz, 1H); 7.99 (d,J=8.6 Hz, 0.5H); 8.16 (t, J=8.6 Hz, 1H); 8.34 (m, 1H); 8.74 (d, J=5.5Hz, 1H); 10.9 and 11.4 (2 s, 1H); 13.0 (s, 1H). APCI-MS m/z 380 (M−H)⁻.

EXAMPLE 93 6H-[1,3]Thiazolo[5,4-e]indole-7,8dione8-[N-(3-methoxyphenyl)hydrazone]

Prepared according to Procedure H using6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (Procedure A) and3-methoxyphenylhydrazine hydrochloride in 44% yield. APCI-MS m/z 323(M−H)⁻.

EXAMPLE 94 5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione3-[N-(4-methylphenyl)hydrazone]

5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from3,5-dimethyl-4-hydroxyaniline according to Procedure A: ¹H NMR(DMSO-d₆): δ 2.17 (s, 3H), 2.30 (s, 3H), 6.45 (s, 1H), 8.29 (s, 1H),10.65 (s, 1H); ESI-MS m/z 190 (M−H)⁻. The isatin was combined with4-methylphenylhydrazine hydrochloride according to Procedure H toprovide the title compound in 41% yield. ¹H NMR (DMSO-d6): δ 2.15 (s,3H), 2.24 (s, 3H), 2.43 (s, 3H), 6.46 (s, 1H), 7.16 (m, 4H), 7.88 (s,1H), 10.64 (s, 1H 12.85 (s, 1H). APCI-MS m/z 294 (M−H, 45%).

Example 95 (Z)-3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-{N-[4-(trifluoromethyl)phenyl]hydrazone}

Prepared according to Procedure H with 4-trifluoromethylphenylhydrazinehydrochloride in 32% yield. ¹H NMR (DMSO-d₆): δ 7.26 (d, J=8.7 Hz, 1H);7.59 and 7.83 (ABq, J=8.4 Hz, 4H); 7.89 (brd d, J=8.7 Hz, 1H); 10.9 (s,1H); 13.0 (s, 1H). APCI-MS m/z 345 (M−H)⁻.

EXAMPLE 96 6H-[1,3]Thiazolo[5,4-e]indole-7,8dione8-[N-(3-fluorophenyl)hydrazone](Z-isomer)

6H-1-Thia-3,6-diaza-as-indacen-7,8-dione (Procedure A, 50 mg, 0.25 mmol)was combined with 3-fluorophenylhydrazine hydrochloride (50 mg, 0.3mmol) in 2 ml of ethanol and heated at 70° C. for 6 hrs. The product wascollected by filtration of the hot solution, washing with ethanol anddiethyl ether, to give 47 mg (60%) of the title compound as a brownsolid. ¹H NMR (DMSO-d₆): δ 6.82 (t, J=8.7 Hz, 1H); 7.10 (d, J=8.6 Hz,1H); 7.37 (m, 2H); 7.41 (dd, 1H); 7.97 (d, J=8.6 Hz, 1H); 9.25 (s, 1H);11.2 (s, 1H). ES-MS m/z 311 (M−1)⁻.

EXAMPLE 97 (Z)-6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(4-fluorophenyl)hydrazone]

Prepared according to Example 96 with6H-1-thia-3,6-diaza-as-indacen-7,8-dione (Procedure A) and4-fluorophenylhydrazine hydrochloride in 49% yield. ¹H NMR (DMSO-d₆): δ7.11 (d, J=8.6 Hz, 1H); 7.25 (t, J=8.8 Hz, 2H); 7.52 (dd, J=4.8, 8.8 Hz,2H); 7.94 (d, J=8.6 Hz, 1H); 9.27 (s, 1H); 11.2 (s, 1H); 12.6 (s, 1H).ES-MS m/z 311 (M−1)⁻.

EXAMPLE 98 (Z)-6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(4-bromophenyl)hydrazone]

Prepared according to Example 96 with6H-1-thia-3,6-diaza-as-indacen-7,8-dione (Procedure A) and4-bromophenylhydrazine hydrochloride in 62% yield. ¹H NMR (DMSO-d₆): δ7.16 (d, J=8.5 Hz, 1H); 7.50 and 7.62 (Abq, J=8.8 Hz, 4H); 8.02 (d,J=8.5 Hz, 1H); 9.33 (s, 1H); 11.3 (s, 1H); 12.6 (s, 1H). ES-MS m/z 371,373 (M−1)⁻.

Procedure J—Method for preparation of a solution phase librarycontaining compounds of the invention

Set forth below are a selected number of synthesis examples thatillustrate the solution library techniques that can be used to obtainthe compounds of the invention. It is believed that One of ordinaryskill in the art can follow this procedure or modify it accordinglywithout undue experimentation in order to obtain the substitutionsdisclosed above. The following examples are illustrative examples of thesolution phase synthesis, not intended to limit the scope of theinvention in any way.

Synthesis of Intermediates

5-Bromo-7-azaoxindole

a) 3,3,5 Tribromooxindole

A solution of 3,3-dibromo-7-azaoxindole (5.0 g, 13.4 mmol) in tert-BuOH(100 mL) and water (100 mL) is stirred at room temperature and bromine(5.5 g, 34.3 mmol) is added dropwise over 20 min. A saturated aqueoussolution of sodium bicarbonate (approx. 15 mL) is added dropwise over 30min to raise the pH of the solution to 6.5. The yellow solid formed iscollected by filtration. The filtrate is condensed to approx. 100 mL andextracted with CHCl₃ (2×50 mL). The combined organic extracts are driedover anhydrous magnesium sulfate and the solvent is evaporated underreduced pressure to leave a yellow solid. The solids are combined anddried under vacuum to give 3,3,5 tribromooxindole as a yellow solid,6.25 g (98%). ¹H NMR (CDCl₃) δ 9.4 (br s, 1H), 8.28 (d, 1H, J=2 Hz),7.95 (d, 1H, J=2 Hz).

b) 5-Bromo-7-azaoxindole

A solution of 3,3,5-tribromooxindole (5.0 g, 13.4 mmol) in fresh THF(100 mL) is stirred at room temperature and a saturated aqueous solutionof ammonium chloride (100 mL) is added. The flask is placed in a waterbath and activated zinc dust (15.0 g, 230 mmol) is added. The mixture isstirred for 20 min and the zinc is removed by filtration through a padof diatomaceous earth. The organic layer is separated and the aqueouslayer is extracted with THF (20 mL). The combined organic layers werewashed with saturated brine solution, dried over anhydrous magnesiumsulfate and the solvent removed under reduced pressure. The brownresidue is triturated with water (20 mL) and the tan solid is collectedby filtration and dried under vacuum to give 5-bromo-7-azaoxindole as atan solid, 2.02 g (71%). ¹H NMR (DMSO-d₆) δ 11.13 (s, 1H), 8.15 (s, 1H),8.76 (s, 1H), 3.57 (s, 2H). MS (AP −ve) 211 (100) (M−H).

5-Phenyl-7-azaoxindole

To a stirred mixture of 5-bromo-7-azaoxindole (213 mg, 1 mmol) andphenylboronic acid (183 mg, 1.5 mmol) in toluene (6 ml) and ethanol (6ml) were added 1 M sodium carbonate solution (2.5 ml, 2.5 mmol), lithiumchloride (127 mg, 3 mmol) anddichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol) under N₂atmosphere. The reaction mixture was heated to reflux at 95° C. for 18hours. The reaction mixture was diluted with chloroform (50 ml) andwashed with brine (20 ml). The aqueous layer was thoroughly extractedwith chloroform. The combined organic layers were dried over anhydrousMgSO₄, filtered and evaporated under vacuum to give crude product.Trituation of the crude product with diethyl ether yielded5-phenyl-7-azaoxindole as a yellow solid (108 mg, 51.4%). ¹H NMR(DMSO-d₆): δ 11.04 (s, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 7.60 (d, 2H,J=7.4 Hz), 7.44 (t, 2H, J=7.4 Hz), 7.32 (t, 1H, J=7.4 Hz), 3.58 (s, 2H).MS (−ve APCI): 210 (48, M⁺), 209 (100, M−H).

5-(Furan-2-yl)-7-aza-oxindole

5-Bromo-7-azaoxindole (0.75 g, 3.52 mmol), 2-tributyltinfuran (1.26 g,3.52 mmol), tetraethylammonium chloride hydrate (1.94 g, 10.6 mmol) werecombined and dissolved in acetonitrile (10 mL) at room temperature underan atmosphere of nitrogen. Bistriphenylphosphine dichloropalladium (II)(0.25 g, 0.35 mmol) was added and the reaction was warmed to 85° C. for16 h. The reaction was cooled to room temperature and diluted withaqueous KF (10%, 60 mL). This was stirred for 20 minutes and thendiluted with EtOAc (60 mL). The biphasic system was passed throughcelite, the layers separated, and the volatiles removed in vacuo. Theresulting residue was triturated with diethyl ether and the solids werecollected by filtration to afford a light yelow solid (0.28 g, 36%yield). 1H NMR 300 MHz (DMSO-d₆) δ 11.18 (bs, 1H); 8.45 (s, 1H); 7.92(s, 1H); 7.79 (s, 1H); 6.95 (d, 1H); 6.60 (d, 1H); 3.64 (s, 2H). APCIm/z 201 (M+1).

5-(3-Thienyl)-7-aza-oxindole

5-Bromo-7-azaoxindole (0.20 g, 0.94 mmol), 3-tributyltinthiophene (0.42g, 1.12 mmol), tetraethylammonium chloride hydrate (0.16 g, 0.94 mmol)were combined and dissolved in acetonitrile (10 mL) at room temperatureunder nitrogen. Bistriphenylphosphine dichloropalladium (II) (0.033 g,0.047 mmol) was added and the reaction was warmed to 85° C. for 20 h.Fresh catalyst was added to the reaction mixture, Bistriphenylphosphinedichloropalladium (II) (0.033 g, 0.047 mmol) and the reaction continuedto stir at 85° C. for 24 h. The reaction was cooled to room temperatureand diluted with water (20 mL) and EtOAc (20 ml). The biphasic systemwas passed through celite and the layers were separated. he organiclayer was washed with brine (10 mL) and dried over sodium sulfate. Thevolatiles ere removed in vacuo. The resulting residue was trituratedwith diethyl ether and collected by filtration (0.16 g, 80% yield).). 1HNMR 400 MHz (DMSO-d₆) δ 11.03 (bs, 1H); 8.43 (s, 1H); 7.92 (s, 1H); 7.84(s, 1H); 7.60 (m, 1H); 7.53 (d, 1H); 3.58 (s, 2H).

5-Carboethoxy-7-azaoxindole

To a mixture of 5-bromo-7-azaoxindole (213 mg, 1 mmol) indimethylsulfoxide (1 ml) and ethanol (5 ml) in Parr bomb were addedtriethylamine (0.31 ml, 2.25 mmol), palladium acetate (33.7 mg, 0.15mmol), and 1,3-(bisdiphenylphosphino)propane (61.9 mg, 0.15 mmol).Carbon monoxide gas (40 atm) was applied and the reaction mixture washeated at 95° C. for 18 hours with vigorously stirring. The reactionmixture was diluted with diethyl ether (50 ml) and washed with water (10ml). The aqueous layer was thoroughly extracted with diethyl ether. Thecombined organic layers were dried over anhydrous MgSO₄, filtered andevaporated under vacuum to give crude product. Trituation of the crudeproduct with methanol yielded 5-(carboethoxy)-7-azaoxindole as a tansolid (53 mg, 25.7%). ¹H NMR (DMSO-d₆): δ 11.39 (s, 1H), 8.62 (s, 1H),7.95 (s, 1H), 4.27 (q, 2H, J=7 Hz), 3.59 (s, 2H), 1.28 (t, 3H, J=7 Hz).MS (−ve APCI): 205 (4, M−H).

6-Chloro-7-azaoxindole

a) 6-Chloro-7-aza-3,3-dibromooxindole

6-Chloro-7-azaindole was prepared according to the procedure of Minakataet al; Synthesis, 1992, 661-663. To a stirred solution of 1.32 g (8.7mmol) of 6-chloro-7-azaindole in tert-butanol (80 mL) was added 9.9 g(28 mmol) of 90% pyridine hydrobromide perbromide reulting in a thickyellow precipitate forming immediately. The reaction was concentratedand the crude chromatographed on silica gel eluting with hexane to 90%hexane/10% EtOAc gradient to give 2.36 g of the title compound as awhite solid, containing about 30% of5-bromo-6-chloro-7-aza-3,3-dibromooxindole as an inseparable impurity.¹H NMR (CDCl₃) δ 7.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 9.0(bs, 1H). (5-Bromo-6-chloro-7-aza-3,3- dibromooxindole, 8.05 (s, 1H),9.0 (bs, 1H).

b) 6-Chloro-7-azaoxindole

A solution of 2.36 g (7.26 mmol) of the mixture of6-chloro-7-aza-3,3-dibromooxindole and5-bromo-6-chloro-7-aza-3,3-dibromooxindole in THF (70 mL) and saturatedammonium chloride solution (70 mL) was treated with 6 g (92 mmol) ofpowdered zinc. After stirring for 2 h another 6 g (92 mmol) portion ofzinc was added and stirring continued another 2 h. The zinc was filteredoff and washed with ether. Ether phase separated and the aqueous phasewashed twice with a 1:1 mixture of THF/ether. Combined ether fractionswere dried over magnesium sulfate, filtered and concentrated. The crudewas loaded onto 7.5 g of silica gel and chromatographed on silica geleluting with 90% hexane/10% ethyl acetate to a 66% hexane/33% ethylacetate gradient to give 0.647 g of the title compound, plus 0.243 g of5-bromo-6-chloro-7-azaoxindole. ¹H NMR (DMSO-d₆): δ 3.57 (s, 2H), 7.04(d, J=7.6 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 11.2 (bs, 1H).

7-Azaoxindole

a) 3,3-Dibromo-7-azaoxindole

A solution of 7-azaindole (4.0 g, 34 mmol) in tert-BuOH (200 mL) isstirred at room temperature and pyridinium perbromide (32.5 g, 0.1 mol)is added in portions over 30 min. and the reaction mixture is stirredfor 3 h. Pyridinium perbromide (10.8 g, 33 mmol) is added and themixture is stirred for a further 2 h. The tert-BuOH is evaporated undereduced pressure and the residue is partitioned between water (300 mL)and EtOAc (300 mL). The organic layer is separated and the aqueous layeris extracted with EtOAc. The combined organic layers are washed withwater (2×50 mL), and brine. The organic layer is dried over anhydrousMgSO₄, filtered and the solvent evaporated. Trituration of the residuewith CH2Cl2 gives a white solid which is collected by filtration anddried under vacuum to give 3,3-dibromo-7-azaoxindole, 8.35 g. ¹H-NMR(DMSO-d₆) δ 11.99 (s, 1H), 8.21 (dd, 1H, J=5.1, 1.5 Hz), 8.00 (dd, 1H,J=7.5, 1.5 Hz), 7.17 (dd, 1H, J=7.5, 5.1 Hz). MS (+ve ES) 293 (28),(M+H), 147 (100).

b) 7-Azaoxindole

A solution of 3,3-dibromo-7-azaoxindole (2.0 g, 7.2 mmol) in THF (50 mL)is stirred at room temperature and a saturated aqueous solution of NH₄Clis added. Activated zinc powder is added and the reaction mixture isstirred for 2 h. The zinc is removed by filtration through a pad ofdiatomaceous earth and the organic layer is separated. The aqueous layeris extracted with THF (10 mL) and the combined organic layers are driedover anhydrous MgSO₄, filtered and evaporated. The residue is slurriedin 10:1 CHCl3:MeOH (15 mL) and filtered through a pad of silica gel andthe filtrate is evaporated. The residue is triturated with water and thesolid is collected by filtration and dried under vacuum to give7-azaoxindole, 0.668 g (70%). ¹H NMR (DMSO-d₆) δ 10.94 (s, 1H), 8.02 (d,1H, J=5.2 Hz), 7.52 (d, 1H, J=6.8 Hz), 6.90 (dd, 1H, J=6.8, 5.2 Hz),3.53 (s, 2H). MS(AP−ve) 133 (100) (M−H)

4-Aza-oxindole

a) Diethyl (3-nitropyridin-2-yl)-malonate

Sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefullywashed with hexanes under nitrogen before the addition of DMSO (115 mL).Diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min andthe mixture was stirred for an additional 30 min at room temperature.2-Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction andthe reaction was placed in a pre-heated oil bath set to 100° C. for 15min. The reaction was cooled to room temperature and poured into aqueousammonium chloride (saturated solution, 150 mL). The aqueous solution wasextracted with EtOAc:Hexanes (1:1) four times (200 mL each) and theorganic layers were combined. The organics were concentrated to afford asolid that was recrystallized from a minimal amount of EtOAc:Hexanes(1:1) (12.5 g, 70% yield). APCI MS m/z 281 (M−1).

b) Ethyl 2-(3-nitro-pyridin-2-yl)-acetate

Diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 0.044 mol) was dissolvedin DMSO (150 mL) and water (0.79 mL, 0.044 mol) and lithium chloride(4.65 g, 0.11 mol) were added at room temperature under nitrogen. Thereaction was warmed to 100° C. 12 h and more lithium chloride (1 g) wasadded to the reaction. The reaction was heated for another 5 hours andcooled to room temperature. Brine (150 mL) was added to the reactionbefore extracting with EtOAc (3×, 275 mL each). The organics werecombined and dried over sodium sulfate, then concentrated in vacuo. Theresulting residue was triturated with diethyl ether and collected byfiltration (8.6 g, 92% yield). 1H NMR 400 MHz (DMSO-d6) δ 8.83 (m, 1H);8.53 (m, 1H); 7.65 (m, 1H); 4.23 (s, 2H); 4.07 (m, 2H); 1.16 (m, 3H).

c) Ethyl 2-(3-amino-pyridin-2-yl)-acetate

Under an atmosphere of nitrogen, Pd/C (10%, 1.36 g) was charged to around bottome flask. Ethyl 2-(3-nitro-pyridin-2-yl)-acetate (8.6 g, 0.41mol) was dissolved in ethanol (200 mL) and added to the reaction vessel.The reaction was placed under an atmosphere of hydrogen and stirred atroom temperature for 30 min. The reaction was filtered through celiteand the filtrate was concentrated in vacuo to afford the product as atan solid (6.94 g, 94% yield).

d) 4-Azaoxindole

Ethyl 2-(3-amino-pyridin-2-yl)-acetate (6.94 g, 0.038 mol) was dissolvedin diethyl ether (100 mL) at room temperature. Hydrochloric acid (2M, 35mL) was added and the reaction was stirred for 30 minutes. The volatileswere removed to afford a brown solid that was re-crystallized fromethanol and diethyl ether (4.0 g, 62% yield). 1H NMR 400 MHz (DMSO-d₆) δ12.35 (s, 1H); 8.12 (m, 1H); 7.90 (m, 1H); 7.14 (m, 1H); 5.75 (s, 2H).Electrospray MS m/z 135 (M+1).

6-(Furan-2-yl)oxindole

6-Bromo-oxindole (0.40 g, 1.88 mmol), 2-tributyltinfuran (0.71 mL, 2.26mmol), and tetraethylammonium chloride hydrate (0.31 g, 1.88 mmol) werecombined and dissolved in acetonitrile (15 mL). The palladium catalyst,bistriphenylphosphinedichloropalladium (II) (0.66 g, 0.09 mmol) wasadded and the reaction was warmed to 85° C. under nitrogen for 20 h. Thereaction was cooled to room temperature and diluted with water (15 mL)before passing the mixture through celite. The pad of celite was washedwith EtOAc and the filtrates were combined and separated. The aqueouslayer was washed with EtOAc (2×20 mL each). The combined organic phaseswere washed with brine and dried over sodium sulfate. The volatiles ereremoved in vacuo. The resulting residue was triturated with diethylether and the solid was collected by filtration (0.13 g, 34%). ¹H NMR300 MHz (DMSO-d6) δ 10.5 (s, 1H); 7.75 (s, 1H); 7.30 (m, 2H); 7.11 (s,1H); 6.91 (m, 1H); 6.60 (m, 1H); 3.52 (s, 2H).

Synthesis of Monomers

Monomer 6: 5-Carboethoxy-3-ethoxymethylene-7-azaoxindole

(Procedure J-1)

5-Carboethoxy-7-azaoxindole (0.040 g, 0.19 mmol) anddiethoxymethylacetate (0.16 mL, 0.97 mmol) were combined and dissolvedin acetic acid (1 mL). The reaction was warmed to 110° C. and stirred atthis temperature for 1 h. The reaction was cooled to room temperatureand diethyl ether was added to precipitate a beige solid that wascollected by filtration (35 mg, 69% yield). ¹H NMR 400 MHz (DMSO-d6) δ11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H);4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).

Monomer 7: 3-Dimethylaminomethylene-6-phenyloxindole

(Procedure J-2)

6-Phenyloxindole (0.053 mg, 0.25 mmol) and dimethylformamidedi-t-butylacetal (0.08 mL, 0.32 mmol) were combined and dissolved inDMF. The reaction mixture was stirred at room temperature for 4 hours.The volatiles were removed in vacuo and the resulting residue wastriturated with diethyl ether. The solids were collected by filtration(50 mg, 75% yield). ). ¹H NMR 400 MHz (DMSO-d6) mixture of E and Zisomers: δ 10.09 (s, 1H); 10.02 (s, 1H); 7.59-7.51 (m, 4H); 7.45-7.22(m, 10H); 7.10-7.05 (m, 2H); 6.98 (s, 1H); 6.91 (s, 1H); 3.29 (s, 12H).

Monomer 1: 3-Ethoxymethylene-5-phenyl-7-azaoxindole

Synthesized according to Procedure J-1. ¹H NMR 400 MHz (DMSO-d6) δ 10.93(s, 1H); 8.24 (s, 1H); 7.86-7.82 (m, 2H); 7.62-7.56 (m, 2H); 7.44 (m,2H); 7.34 (m, 1H); 4.40 (m, 2H); 1.35 (m, 3H).

Monomer 2: 3-Ethoxymethylene-5-(2-furanyl)-7-azaoxindole

Synthesized according to Procedure J-1. ¹H NMR 400 MHz (DMSO-d6) δ 10.96(s, 1H); 8.36 (s, 1H); 7.87-7.84 (m, 2H); 7.72 (s, 1H); 6.87 (d, 1H);6.56 (m, 1H); 4.42 (m, 2H); 1.36 (m, 3H).

Monomer 3: 3-Ethoxymethylene-5-(3-thienyl)-7-azaoxindole

Synthesized according to Procedure J-1. ¹H NMR 400 MHz (DMSO-d6) δ 10.89(s, 1H); 8.33 (s, 1H); 7.88 (s, 1H); 7.84 (s, 1H); 7.79 (s, 1H); 7.62(m, 1H); 7.49 (d, 1H); 4.40 (m, 2H); 1.36 (m, 3H).

Monomer 4: 5-Bromo-3-ethoxymethylene-7-azaoxindole

Synthesized according to Procedure J-1. ¹H NMR 400 MHz (DMSO-d6) δ 11.02(s, 1H); 8.07 (s, 1H); 7.88 (s, 1H); 7.71 (s, 1H); 4.40 (m, 2H); 1.34(m, 3H).

Monomer 5: 6-Chloro-3-ethoxymethylene-7-azaoxindole

Synthesized according to Procedure J-1. ¹H NMR 400 MHz (DMSO-d6) δ 11.06(s, 1H); 7.84 (s, 1H); 7.63 (d, 1H); 6.98 (d, 1H); 4.39 (m, 2H); 1.32(m, 3H).

Monomer 8: 3-Dimethylaminomethylene-6-(2-furanyl)oxindole

Synthesized according to Procedure J-2. ¹H NMR 400 MHz (DMSO-d6) mixtureof E and Z isomers: δ 10.10 (s, 1H); 10.03 (s, 1H); 7.64 (s, 1H); 7.61(s, 1H); 7.56 (s, 1H); 7.38 (s, 1H); 7.37 (d, 1H); 7.26 (d, 1H); 7.14(s, 1H); 7.12 (s, 1H); 7.03 (s, 1H); 6.96 (s, 1H); 6.72 (d, 1H); 6.67(d, 1H); 6.52 (s, 1H); 6.49 (s, 1H); 3.29 (s, 12H)

Monomer 9: 3-Dimethylaminomethylene-7-azaoxindole

This monomer was generated in situ (during library synthesis) from7-aza-oxindole and dimethylformamide di-t-butylacetal in DMF.

Monomer 10: 3-Dimethylaminomethylene4-azaoxindole

This monomer was generated in situ (during library synthesis) from4-aza-oxindole and dimethylformamide di-t-butylacetal in DMF.

Representative Amine Monomers are shown in Table 6.

Monomer Code Structure A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Solution Phase Library Synthesis

Stock solutions (0.037M) were prepared for each set of monomers. Forexample, 35 mg of Monomer 1 was dissolved in 3.5 mL of ethanol. Eachmonomer was prepared in a separate solution and carefully labeled 1through 8. For the amine set, a slight excess of stock solution wasprepared. For example, 20.4 mg was dissolved in 4.0 mL of methanol. Eachamine as prepared in a separate solution and carefully labeled A throughP.

Monomer 9 and Monomer 10 were generated in situ by preparing stocksolutions of the corresponding aza-oxindole. For example, 20.1 mg of4-aza-oxindole was dissolved in 4.0 mL of ethanol. Both of theprecursors for monomers 9 and 10 were transferred (0.20 ml/well) to a96-well dry heating block (vwrBRAND Dry Block Heater, cat #13259-066)according to the map below where M represents the monomer and Arepresents the amine. The ethanol was evaporated off at 50° C. until itwas clear that there was no solvent remaining. DMF (0.20 mL) was addedfollowed by the addition of dimethylformamide di-t-butylacetal (0.003mL) and this remained at room temperature for 1 h.

Monomers 1 through 8 (0.20 mL/well) were transferred to the appropriatewells in the dry block heater according to the plate map below. Afterthe in situ conversion of monomer 9 and 10 was complete, the aniline set(0.20 mL/well) was transferred to the appropriate wells according to theplate map below. The plates were heated to 70° C. for 4 h and then thereaction was cooled to 40° C. and heating was continued for another 16h. Ethanol was added as necessary to keep a constant reaction volume inthe wells.

Plate 1 M1-AA M1-AI M2-AA M2-AI M3-AA M3-AI M4-AA M4-AI M5-AA M5-AIM1-AB M1-AJ M2-AB M2-AJ M3-AB M3-AJ M4-AB M4-AJ M5-AB M5-AJ M1-AC M1-AKM2-AC M2-AK M3-AC M3-AK M4-AC M4-AK M5-AC M5-AK M1-AD M1-AL M2-AD M2-ALM3-AD M3-AL M4-AD M4-AL M5-AD M5-AL M1-AE M1-AM M2-AE M2-AM M3-AE M3-AMM4-AE M4-AM M5-AE M5-AM M1-AF M1-AN M2-AF M2-AN M3-AF M3-AN M4-AF M4-ANM5-AF M5-AN M1-AG M1-AO M2-AG M2-AO M3-AG M3-AO M4-AG M4-AO M5-AG M5-AOM1-AH M1-AP M2-AH M2-AP M3-AH M3-AP M4-AH M4-AP M5-AH M5-AP

Plate 2 M6-AA M6-AI M7-AA M-7AI M8-AA M8-AI M9-AA M9-AI M10-AA M10-AIM6-AB M6-AJ M7-AB M7-AJ M8-AB M8-AJ M9-AB M9-AJ M10-AB M10-AJ M6-ACM6-AK M7-AC M7-AK M8-AC M8-AK M9AC M9-AK M10-AC M10-AK M6-AD M6-AL M7-ADM7-AL M8-AD M8-AL M9-AD M9-AL M10-AD M10-AL M6-AE M6-AM M7-AE M7-AMM8-AE M8-AM M9-AE M9-AM M10-AE M10-AM M6-AF M6-AN M7-AF M7-AN M8-AFM8-AN M9-AF M9-AN M10-AF M10-AN M6-AG M6-AO M7-AG M7-AO M8-AG M8-AOM9-AG M9-AO M10-AG M10-AO M6-AH M6-AP M7-AH M7-AP M8-AH M8-AP M9-AHM9-AP M10-AH M10-AP

Upon completion of the reaction, methanol (1.0 mL) was added to eachwell. Using a multi-pipettor, the contents of the reaction wells weretransferred to the appropriate wells of a 96-well (Beckmann) plate. Thevolatiles were removed using a nitrogen flow to substantially reduce thevolume of solvent, followed by placing the plates in a vacuum dryingoven at 70° C. under 15 mmHg of pressure. The average weight of productdetermined for plate 1 was 1.91 mg/well (70% conversion). The averageweight of product determined for plate 2 was 1.78 mg/mL (70%conversion). All of the wells were analysed by LC-MS.

A Micromass Platform II mass spectrometer equipped with an electrosprayion source was used to acquire low resolution LC-MS data for thesamples. The system software runs on a PC computer with the Microsoftoperating system, and consists of Masslynx v3.1 and Openlynx v3.1software packages. The mass spectrometer inlet system was comprised of aHewlett Packard 1100 HPLC Chromatograph, a Gilson 215 autosampler, and aHewlett Packard 1100 photo-diode array detector. A Supelco ABZ+ 5 cmcolumn was used to provide separations prior to electrospray ionization.The HPLC was programmed as follows:

Time % A % B Flow Rate 0.0 min 85 15 0.6 ml/min 3.0 min 25 75 0.6 ml/min4.0 min 0 100 0.6 ml/min 5.0 min 0 100 0.6 ml/min

The data were processed automatically using standard peak detectionparameters provided by the Openlynx software.

A Micromass LCT bench-top mass spectrometer equipped with anelectrospray ionization source was used to obtain accurate mass (highresolution) data. The LCT utilizes two hexapole RF lenses to transferions from the source to an orthogonal acceleration time-of-flight (TOF)analyser. The ions emerging from the analyser are detected using a dualmicrochannel plate detector and ion counting system. The system softwareruns on a PC computer with the Microsoft operating system, and consistsof Masslynx v3.2 and Openlynx v3.2 software packages. The massspectrometer inlet system is comprised of a Waters Alliance 2690Separations Module, Waters 2700 autosampler, Waters 996 photo-diodearray detector and Valco column switching device. A mobile phase flowrate of 1 ml/min exits the Alliance 2690 and is reduced to a massspectrometer flow rate of 20 ul/min using an Acurate flow splitter. Alock mass solution at a flow rate of 4 ul/min is added to thespectrometer flow via a Harvard syringe pump and a tee piece placedimmediately before the electrospray probe. The instrument resolution wasdetermined by acquiring a spectrum and measuring the full peak width thalf peak height (FWHH). The instrument was tuned to provide aresolution of 4600 to 5000 (FWHH). The instrument was calibrated usingthe ions of polyethylene glycol (PEG) as reference standards. The lockmass used [3,5-Dil-Tyr, Ala,N-Me-Phe, Gly-0I] Enkephalin(MH+C₂₆H₃₄I₂N₅O₆=766.0599) at a concentration of 5 ng/μl.

Following are examples of the invention prepared in the solution phaselibrary with accompanying high resolution or low resolution massspectral data.

EXAMPLE 73 3-{[(Z andE)-(2-Oxo-6-phenyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzamide.Accurate mass M+H=356.1388 (mmu error 1.0) EXAMPLE 74 Diethyl 4-{[(Z andE)-(2-oxo-6-phenyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzylphosphonate.Accurate mass M+H=463.1952 (mmu error 3.4) EXAMPLE 75 3-{[(Z andE)-(2-Oxo-6-phenyl-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzonitrile.Accurate mass M+H=338.1289 (mmu error 0.3) EXAMPLE 76 3-{(Z andE)-[2-(2-Hydroxyethyl)anilino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H 357.1595 (mmu error 0.7) Example 77 3-{(Z andE)-[3-(Hydroxymethyl)anilino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=343.1438 (mmu error 0.7) EXAMPLE 78 3-[(Z andE)-(2-Methoxyanilino)methylidene]-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=343.1442 (mmu error 0.3) Example 79 3-{(Z andE)-[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-6-phenyl-1H-indol-2-one.Accurate mass M+H=409.1645 (mmu error 1.9) EXAMPLE 80 3-[(Z andE)-(4-Iodoanilino)methylidene]-6-phenyl-1H-indol-2-one. Accurate massM+H=439.0246 (mmu error 1.9) EXAMPLE 81 3-({(Z andE)-6-(2-Furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)benzamide.Accurate mass M+H=346.1188 (mmu error 0.2) EXAMPLE 82 Diethyl 4-({(Z andE)-[6-(2-furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)benzylphosphonate.Accurate mass M+H=453.1755 (mmu error 2.3) EXAMPLE 83 3-({(Z andE)-[6-(2-Furyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}amino)benzonitrile.LC-ES-MS (M+H)=328 EXAMPLE 84 6-(2-Furyl)-3-{(Z andE)-[2-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=347.1377 (mmu error 1.7) EXAMPLE 85 6-(2-Furyl)-3-{(ZandE)-[3-(hydroxymethyl)anilino]methylidene)-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=333.1227 (mmu error 1.0) EXAMPLE 86 6-(2-Furyl)-3-[(Zand E)-(2-methoxyanilino)methylidene]-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=333.1234 (mmu error 0.4) EXAMPLE 87 6-(2-Furyl)-3-{(ZandE)-[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1H-indol-2-one.Accurate mass M+H=399.1444 (mmu error 1.1) EXAMPLE 88 6-(2-Furyl)-3-[(Zand E)-(4-iodoanilino)methylidene]-1H-indol-2-one. Accurate massM+H=429.0031 (mmu error 2.7) EXAMPLE 993-{[(2-Oxo-5-phenyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide.Accurate mass M+H=357.1339 (mmu error 1.2) EXAMPLE 100 Diethyl4-{[(2-oxo-5-phenyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate.Accurate mass M+H=464.1918 (mmu error 2.0) EXAMPLE 1013-{[(2-Oxo-5-phenyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile.Accurate mass M+H=339.1237 (mmu error 0.8) Example 1023-{[2-(2-Hydroxyethyl)anilino]methylidene}-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=358.1534 (mmu error 2.1) EXAMPLE 1033-{[3-(Hydroxymethyl)anilino]methylidene}-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=344.1377 (mmu error 2.1) EXAMPLE 1043-[(2-Methoxyanilino)methylidene]-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=344.1386 (mmu error 1.2) EXAMPLE 1053-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-5-phenyl-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=410.1597 (mmu error 1.9) EXAMPLE 1063-[(4-Iodoanilino)methylidene]-5-phenyl-1H-pyrrolo[2,3b]pyridin-2-one.Accurate mass M+H=440.0218 (mmu error 0.0) EXAMPLE 1073-({[5-(2-Furyl)-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene]methyl}amino)benzamide.Accurate mass M+H=347.1135 (mmu error 0.8) EXAMPLE 108 Diethyl4-({[5-(2-furyl)-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene]methyl}amino)benzylphosphonate.Accurate mass M+H 454.1724 (mmu error 0.7) EXAMPLE 1093-({[5-(2-Furyl-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene]methyl}amino)benzonitrile.Accurate mass M+H=329.1017 (mmu error2.1) EXAMPLE 1105-(2-Furyl)-3-{[2-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=348.1333 (mmu error 1.4) EXAMPLE 1115-(2-Furyl)-3-{[3-(hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2one.Accurate mass M+H=334.1168 (mmu error 2.3) EXAMPLE 1125-(2-Furyl)-3-[(2-methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=334.1177 (mmu error 1.4) EXAMPLE 1135-(2-Furyl)-3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=400.1394 (mmu error 1.5) EXAMPLE 1145-(2-Furyl)-3-[(4-iodoanilino)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=430.0008 (mmu error 0.3) EXAMPLE 1153-({[2-Oxo-5-(3-thienyl)-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene]methyl}amino)benzamide.Accurate mass M+H=363.0903 (mmu error 1.2) EXAMPLE 116 Diethyl4-({[2-oxo-5-(3-thienyl)-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene]methyl}amino)benzylphosphonate.Accurate mass M+H=470.1497 (mmu error 0.6) EXAMPLE 1173-({[2-Oxo-5-(3-thienyl)-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene]methyl}amino)benzonitrile.Accurate mass M+H=345.0800 (mmu error 0.9) EXAMPLE 1183-[{2-(2-Hydroxyethyl)anilino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=364.1098 (mmu error 2.1) EXAMPLE 1193-[{3-(Hydroxymethyl)anilino]methylidene}-5-(3-thienyl)-1,3-dihydro2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=350.0959 (mmu error 0.4) EXAMPLE 1203-[(2-Methoxyanilino)methylidene]-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=350.0946 (mmu error 1.7) EXAMPLE 1213-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=416.1172 (mmu error 0.8) EXAMPLE 1223-[(4-Iodoanilino)methylidene]-5-(3-thienyl)-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=445.9771 (mmu error 1.2) EXAMPLE 1233-{[(5-Bromo-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide.Accurate mass M+H=359.0134 (mmu error 0.9) EXAMPLE 124 Diethyl4-{[(5-Bromo-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate.Accurate mass M+H=466.0730 (mmu error 0.0) EXAMPLE 1253-{[(5-Bromo-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile.Accurate mass M+H=341.0033 (mmu error 0.4) EXAMPLE 1265-Bromo-3-{[2-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=360.0337 (mmu error 1.0) EXAMPLE 1275-Bromo-3-{[3-(hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=346.0176 (mmu error 1.4) EXAMPLE 1285-Bromo-3-[(2-methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=346.0169 (mmu error 2.1) EXAMPLE 1295-Bromo-3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=412.0388 (mmu error 2.0) EXAMPLE 1305-Bromo-3-[(4-iodoanilino)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=441.9002 (mmu error 0.8) EXAMPLE 1313-{[(6-Chloro-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide.Accurate mass M+H=315.0633 (mmu error 1.5) EXAMPLE 132 Diethyl4-{[(6-chloro-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate.Accurate mass M+H=422.1234 (mmu error 0.2) EXAMPLE 1333-{[(6-Chloro-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile.Accurate mass M+H=297.0532 (mmu error 1.0) EXAMPLE 1346-Chloro-3-{[2-(2-hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=316.0836 (mmu error 1.6) EXAMPLE 1356-Chloro-3-{[3-(hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=302.0683 (mmu error 1.3) EXAMPLE 1366-Chloro-3-[(2-methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[2,3-b)pyridin-2-one.Accurate mass M+H=302.0667 (mmu error 2.9) EXAMPLE 1376-Chloro-3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=368.0894 (mmu error 1.9) EXAMPLE 1386-Chloro-3-[(4-iodoanilino)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=397.9504 (mmu error 1.2) EXAMPLE 139 Ethyl3-{[3-(aminocarbonyl)anilino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=353.1242 (mmu error 0.7) EXAMPLE 140 Ethyl3-({4-[(diethoxyphosphoryl)methyl]anilino}methylidene)-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=460.1826 (mmu error 1.0) EXAMPLE 141 Ethyl3-[(3-cyanoanilino)methylidene]-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=335.1127 (mmu error 1.6) EXAMPLE 142 Ethyl3-[2-(2-hydroxyethyl)anilino]methylidene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=354.1434 (mmu error 1.9) EXAMPLE 143 Ethyl3-{[3-(hydroxymethyl)anilino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=340.1287 (mmu error 0.9) EXAMPLE 144 Ethyl3-[(2-methoxyanilino)methylidene]-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=340.1285 (mmu error 1.1) EXAMPLE 145 Ethyl3-{[4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=406.1499 (mmu error 1.5) EXAMPLE 146 Ethyl3-[(4-iodoanilino)methylidene]-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=436.0103 (mmu error 1.3) EXAMPLE 1473-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzamide.Accurate mass M+H=281.1024 (mmu error 1.4) EXAMPLE 148 Diethyl4-{[(2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate.Accurate mass M+H=388.1607(mmu error 1.8) EXAMPLE 1493-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzonitrile.Accurate mass M+H=263.0923 (mmu error 0.9) EXAMPLE 1503-{[2-(2-Hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=282.1229 (mmu error 1.2) EXAMPLE 1513-{[3-(Hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=268.1082 (mmu error 0.3) EXAMPLE 1523-[(2-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=268.1082 (mmu error 0.3) EXAMPLE 1533-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=334.1301 (mmu error 0.2) EXAMPLE 1543-[(4-Iodoanilino)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one. Accuratemass M+H=363.9898 (mmu error 0.7) EXAMPLE 1553-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[3,2-b]pyridin-3-ylidene)methyl]amino}benzamide.Accurate mass M+H=281.1035 (mmu error 0.3) EXAMPLE 156 Diethyl4-{[(2-oxo-1,2dihydro-3H-pyrrolo[3,2-b]pyridin-3-ylidene)methyl]amino}benzylphosphonate.LC-ES-MS (M+H)=388 EXAMPLE 1573-{[(2-Oxo-1,2-dihydro-3H-pyrrolo[3,2-b]pyridin-3-ylidene)methyl]amino}benzonitrile.Accurate mass M+H=263.0912 (mmu error 2.0) EXAMPLE 1583-{[2-(2-Hydroxyethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=282.1241 (mmu error 0.0) EXAMPLE 1593-{[3-(Hydroxymethyl)anilino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=268.1079 (mmu error 0.6) EXAMPLE 1603-[(2-Methoxyanilino)methylidene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=268.1083 (mmu error 0.2) EXAMPLE 1613-{[4-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)anilino]methylidene}-1H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=334.1301 (mmu error 0.2) EXAMPLE 1623-[(4-Iodoanilino)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one. Accuratemass M+H=363.9896 (mmu error 0.9) EXAMPLE 163 3-{(Z andE)-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-5-phenyl-1,3dihydro-2H-pyrrolo[2,3-b]pyridin-2one.Accurate mass M+H=394.1645 (mmu error 2.2) EXAMPLE 164 3{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2one.Accurate mass M+H=380.1388 (mmu error 1.0) EXAMPLE 165 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=332.1508 (mmu error 0.3) EXAMPLE 166 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-5-phenyl-1H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=354.1336 (mmu error 1.8) EXAMPLE 167 3-((Z andE)-{[6-(4-Morpholinyl)-3-pyridinyl]amino}methylidene)-5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=400.1754 (mmu error 1.9) EXAMPLE 168 5-(2-Furyl)-3{(ZandE)-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=384.1455 (mmu error 0.5) EXAMPLE 169 5-(2-Furyl)-3-{(ZandE)-[(4-hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=370.1189 (mmu error 0.2) EXAMPLE 170 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-5-(2-furyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=322.1297 (mmu error 0.6) EXAMPLE 171 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-5-(2-furyl)-1H-pyrrolo[2,3-b]pyridin-2-one.LC-ES-MS (M+H)=344. EXAMPLE 172 5-(2-Furyl)-3-((Z andE)-{[6-(4-morpholinyl)-3-pyridinyl]amino}methylidene)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=390.1556 (mmu error 0.9) EXAMPLE 173 3-{(Z andE)-[(1-Methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=400.1231 (mmu error 0.0) EXAMPLE 174 3{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=386.0960 (mmu error 0.3) EXAMPLE 175 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=338.1060 (mmu error 1.5) EXAMPLE 176 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=360.0915 (mmu error 0.3) EXAMPLE 177 3-((Z andE)-{[6-(4-Morpholinyl)-3-pyridinyl]amino}methylidene)-5-(3-thienyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=406.1321 (mmu error 1.6) EXAMPLE 178 5-Bromo-3-{(Z andE)-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=396.0442 (mmu error 1.7) EXAMPLE 179 5-Bromo-3-{(Z andE)-[(4-hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=382.0187 (mmu error 0.3) EXAMPLE 180 5-Bromo-3-{(Z andE)-[(1-ethyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=334.0297 (mmu error 0.5) EXAMPLE 181 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=356.0134 (mmu error 1.2) EXAMPLE 182 5-Bromo-3-((Z andE)-{[6-(4-morpholinyl)-3-pyridinyl]amino}methylidene)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=402.0556 (mmu error 0.8) EXAMPLE 183 6-Chloro-3-{(ZandE)-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=352.0957 (mmu error 0.7) EXAMPLE 184 6-Chloro-3-{(ZandE)-[(4-hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=338.0669 (mmu error 2.7) EXAMPLE 185 6-Chloro-3-{(ZandE)-[(1-ethyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=290.0808 (mmu error 0.0) EXAMPLE 186 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=312.0633 (mmu error 1.8) EXAMPLE 187 6-Chloro-3-((ZandE)-{[6-(4-morpholinyl)-3-pyridinyl]amino}methylidene)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=358.1053 (mmu error 1.7) EXAMPLE 188 Ethyl 3-{(Z andE)-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=390.1556 (mmu error 0.9) EXAMPLE 189 Ethyl 3-{(Z andE)-[(4-hydroxy-1-naphthyl)amino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=376.1289 (mmu error 0.7) EXAMPLE 190 Ethyl 3-{(Z andE)-[(1-ethyl-1H-pyrazol-5-yl)amino]methylidene}-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=328.1403 (mmu error 0.5) EXAMPLE 191 Ethyl 3-[(Z andE)-(1H-benzimidazol-2-ylamino)methylidene]-2-oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=350.1241 (mmu error 1.1) EXAMPLE 192 Ethyl 3-((Z andE)-{[6-(4-morpholinyl)-3-pyridinyl]amino}methylidene)-2-oxo-2,3dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.Accurate mass M+H=396.1655 (mmu error 1.6) EXAMPLE 193 3-{(Z andE)-[(1-Methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=393.1691 (mmu error 2.3) EXAMPLE 194 3-{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=379.1430 (mmu error 1.5) EXAMPLE 195 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=331.1552 (mmu error 0.6) EXAMPLE 196 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-6-phenyl-1H-indol-2-one.Accurate mass M+H=353.1388 (mmu error 1.4) EXAMPLE 197 3-((Z andE)-{[6-(4-Morpholinyl)-3-pyridinyl]amino}methylidene)-6-phenyl-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=399.1809 (mmu error 1.1) EXAMPLE 198 6-(2-Furyl-3-{(ZandE)-(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=383.1498 (mmu error 0.9) EXAMPLE 199 6-(2-Furyl)-3-{(ZandE)-[(4-hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-indol-2-oneEXAMPLE 200 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-6-(2-furyl)-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=321.1342 (mmu error 0.8) EXAMPLE 201 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-6-(2-furyl)-1H-indol-2-one.Accurate mass M+H=343.1192 (mmu error 0.2) EXAMPLE 202 6-(2-Furyl)-3-((ZandE)-{[6-(4-morpholinyl)-3-pyridinyl]amino}methylidene)-1,3-dihydro-2H-indol-2-one.Accurate mass M+H=389.1604 (mmu error 0.8) EXAMPLE 203 3-{(Z andE)-[(1-Methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=318.1347 (mmu error 0.6) EXAMPLE 204 3-{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-oneEXAMPLE 205 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.Accurate mass M+H=256.1195 (mmu error 0.2) EXAMPLE 206 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-oneEXAMPLE 207 3-((Z andE)-{-[6-(4-Morpholinyl)-3-pyridinyl]amino}methylidene)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.A ccurate mass M+H=324.1453 (mmu error 0.7) EXAMPLE 208 3-{(Z andE)-[(1-Methyl-3-phenyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=318.1347 (mmu error 0.7) EXAMPLE 209 3-{(Z andE)-[(4-Hydroxy-1-naphthyl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[(3,2-b]pyridin-2-oneEXAMPLE 210 3-{(Z andE)-[(1-Ethyl-1H-pyrazol-5-yl)amino]methylidene}-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=256.1178 (mmu error 1.9) EXAMPLE 211 3-[(Z andE)-(1H-Benzimidazol-2-ylamino)methylidene]-1H-pyrrolo[3,2-b]pyridin-2oneEXAMPLE 212 3-((Z andE)-{[6-(4-Morpholinyl)-3-pyridinyl]amino}methylidene)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.Accurate mass M+H=324.1449 (mmu error 1.0) Pharmaceutical Formulationand Doses

The compounds of the present invention can be administered in such oral(including buccal and sublingual) dosage forms as tablets, capsules(each including timed release and sustained release formulations),pills, powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. Likewise, they may also be administered in nasal, ophthalmic,optic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscularinhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.1 to about 100 mg/kg of body weightper day, and particularly about 1 to 10 mg/kg of body weight per day.Oral dosage units will generally be administered in the range of from 1to about 250 mg and more preferably from about 25 to about 250 mg. Thedaily dosage for a 70 kg mammal will generally be in the range of about70 mg to 7 grams of a compound of formula I or II.

The dosage to be administered is based on the usual conditions such asthe physical condition of the patient, age, body weight, past medicalhistory, route of administrations, severity of the conditions and thelike. Oral administration is generally preferred for administration to ahuman. In some cases, a relatively lower dose is sufficient and, in somecases, a relatively higher dose or increased number of doses may benecessary. Topical application similarly may be once or more than onceper day depending upon the usual medical considerations. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily. The compounds of the invention can beprepared in a range of concentrations for topical use of about 0.5 toabout 5 mg/ml of suitable solvent. A preferred volume for application tothe scalp is about 2 ml, resulting in an effective dosage delivered tothe patient of about 1 to about 10 mg.

For treatment of chemotherapy-induced alopecia, administration 1 to 2times prior to chemotherapy administration is preferred, with additionalapplications administered as needed. A similar regimen can be pursuedfor treatment of alopecia induced by radiation therapy. Furthermore,preferred compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for Example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containingabout 0.01 to about 99.5%, more particularly, about 0.5 to about 90% ofa compound of the formula (II) in combination with a pharmaceuticallyacceptable carrier.

Parenteral administration can be effected by utilizing liquid dosageunit forms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as aqueousoleaginous medium and sterilizing the suspension or solution.

Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservations and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher ester as forExample flavored aqueous solution, while elixirs are prepared throughmyristyl palmitate or mixtures thereof.

Topical formulations of the present invention may be presented as, forinstance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams. The formulations mayalso contain compatible conventional carriers, such as cream or ointmentbases and ethanol or oleyl alcohol for lotions. Such carriers may bepresent as from about 1% up to about 98% of the formulation. Moreusually they will form up to about 80% of the formulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insulator may be formulated containinga powder mix of a compound of the invention and a suitable powder basesuch as lactose or starch.

The preferred pharmaceutical compositions are those in a form suitablefor oral administration, such as tablets and liquids and the like andtopical formulations.

Biological Data

The compounds of the present invention have valuable pharmacologicproperties. Different compounds from this class are particularlyeffective at inhibiting the VEGF-R2 receptor kinase enzyme atconcentrations which range from 0.0001 to 1 μM and additionally showselectivity relative to other kinases. Substrate phosphorylation assayswere carried out as follows:

VEGFR-2

The peptide substrate used in the VEGFR-2 assay wasbiotin-aminohexyl-EEEEYFELVAKKKK-NH₂. The kinase domain of the enzymewas purified to homogeneity from a baculovirus expression system. Theenzyme was preactivated on ice for 15 min in the presence of 100 μM ATPand 20 mM MgCl₂, and stored at −80° C. until needed for assay. Theactivated enzyme was diluted to 0.4 nM into a 60 μl reaction containing100 mM HEPES, pH 7.5, 5 μM ATP, 10 mM MgCl₂, 5 μM peptide, 0.1 mM DTT,0.05 mg/ml BSA, and an inhibitor at varying concentrations. The controlswere reactions in the presence (negative controls) or absence (positivecontrols) of 50 mM EDTA. Reactions were incubated for 30 min at roomtemperature, and then quenched by the addition of EDTA to 60 mM in 210μl. The quenched samples (190 μl) were transferred to aneutravidin-coated plate (Pierce) and incubated at room temperature for40 min to allow biotinylated peptide to bind to the neutravidin. Theunbound components of the reaction were removed by washing with a platewasher, then 200 μl HRP-PY20 anti-phosphotyrosine antibody conjugate wasadded to each well. After incubation for 40 min, the plate was washed toremove any unbound anitbody. A HRP substrate, K-blue (Neogen) was addedand the reaction was quenched with Red Stop (Neogen) after 20 min. Theabsorbance of the wells was read at A₆₅₀ in a plate reader. IC₅₀ valueswere obtained by fitting raw data to A₆₅₀=V_(MAX)*(1−[I]/IC₅₀+[I])))+b,where b is background.

CDK1 and CDK2

Cyclin dependent protein kinase assays utilized the peptidesBiotin-aminohexyl-MKAKKTPKKAKK and Biotin-aminohexyl-ARRPMSPKKKA-NH₂ asphosphoryl group acceptors. CDK1 and CDK2 were both expressed utilizinga baculovirus expression system and were partially purified to comprise20-80% of total protein, with no detectable competing reactions present.Typically, assays were performed by incubating either enzyme (0.2-10nM), with and without inhibitor, one of the two peptide substrates (1-10nM), [γ-³²P]ATP (1-20 nM), and 10-20 mM Mg²⁺ for periods of timegenerally within the range 10-120 min. Reactions were terminated with0.2-2 volumes of either 20% acetic acid or 50-100 mM EDTA buffered to pH7 (substrate consumption <20%). The buffer employed in enzyme assays waseither 30 mM HEPES 7.4 containing 0.15 M NaCl and 5% DMSO, the buffer 50mM MOPS 7.0 containing 0.15 M NaCl and 5% DMSO, or the buffer 100 mMHEPES pH 7.5 containing 0.1 mg/mL BSA and 5% DMSO. Inhibitors werediluted in 100% DMSO prior to addition into the assay. Detection ofpeptide phosphorylation was accomplished by scintillation countingfollowing either collection of peptide onto phosphocellulose filters(for reactions stopped with acetic acid), collection of peptide in wellsof 96 well plates coated with Streptavidin (Pierce) (reactions werestopped with EDTA), or addition of Avidin coated Scintillant impregnatedbeads (Scintillation Proximity Assays from Amersham, reactions werestopped with EDTA). Counts detected by any of these methodologies minusthe appropriate background (assays with additional 40 mM EDTA or lackingpeptide substrate) were assumed to be proportional to the reactioninitial rates, and IC50s were determined by a least squares fit to theequation CPM=V_(max)*(1−([I]/(K+[I])))+nsb, or pIC50s were determined bya fit to the equation CPM=nsb+(V_(max)−nsb)/(1+(x/10^(x)-pIC50)), wherensb are the background counts.

Tie-2

The peptide substrate used in the Tie-2 assay wasbiotin-aminohexyl-LEAREYRWLGGKKKamide. The kinase domain of the enzymewas purified to homogeneity from a baculovirus expression system. Theenzyme was diluted to 10 nM into a 60 μl reaction containing 100 mMHEPES, pH 7.5, 500 μM ATP, 10 mM MgCl₂, 2 μM peptide, 1 mM DTT, 0.05mg/ml BSA, and an inhibitor at varying concentrations. The controls werereactions in the presence (negative controls) or absence (positivecontrols) of 50 mM EDTA. Reactions were incubated for 30 min at roomtemperature, and then quenched by stopped by 80 μl of 0.15 M EDTA. Thequenched samples (125 μl) were transferred to a Neutravidin plates#15128 and incubated at room temperature for 30-60 minutes, allowing thebiotinylated peptide to bind to the neutravidin on the plates. Theneutravidin plates were then washed with water for 5 times. Europiumconjugated anti-phosphotyrosine antibody, (EG & G Wallac, #CR04-100) (1mg/ml) was diluted 1:10,000 in 1% BSA-0.05% Tween 20-TBS, and 150 μl ofthe diluted antibody was added to each well of the neutravidin plate, sothe phosphorylated peptide was bound with the Europium labelledantibody. After another 30-60 min incubation at room temperature, theplates were washed again with water for 5 times. 150 ul of Enhancemantsolution was then added to each well, dissociating Eu³⁺ rom solid phasebound antibodies to form a homogeneous and highly fluorescentEu-(2-NTA)₃(TOPO)₂₋₃ micellar chelate solution. The plates wereincubated for 10 minutes at room temperature to allow the above process,and fluorescent signal for each well was determined in a Wallac 1420Victor Multilabel Counter with “Europium” protocol.

The kinase activity of all wells was calculated as %S, the percentage ofthe fluorescent counts vs. positive controls after substraction ofnegative controls, as in eq. 1. $\begin{matrix}{{\% \quad S} = {100*\frac{{Counts}_{sample} - {Counts}_{negative}}{{Counts}_{positive} - {Counts}_{negative}}}} & (1)\end{matrix}$

Plots of compound concentration versus %S were constructed. IC50s (K,expressed in units of molarity), the compound concentration at which theenzyme activity was inhibited by 50%, were determined from nonlinearleast squares fits of the data to the simple competitive binding modelof eq. 2.

%S=%S _(max)*(1−(X/(K+X)))+Y2  (2)

Where %S is the experimentally observed count rate at sample compoundconcentration X, %S_(max) is the best fit value for the maximumamplitude of the concentration-response curve, Y₂ is the count rateobserved at infinitely high inhibitor concentration.

c-Fms

c-fms protein kinase assays utilized the peptide substrate,biotin-EAIYMPFAKKK-NH₂, as the phosphoryl group acceptor. The c-fmsintracellular domain was expressed from a baculovirus expression system,as an amino-terminal GST fusion protein, and purified to homogeneityusing Glutathione agarose from Sigma Chemical Co. Maximum activation ofthe enzyme was achieved by preactivation at room temperature for 120 minin the presence of 100 μM ATP and 15 mM MgCl₂, This enzyme stock wasdiluted to 150 nM prior to using in the assay. Typically assays wereperformed in white, opaque, 96-well plates in a 45 ul assay volumeincluding 15 ul 6% DMSO, with or without compounds, 15 ul of thepreactivated, diluted enzyme, and 15 ul of a substrate mixture.Reactions contained 50 mM HEPES, pH 7.5, 1.7 μM ATP, 15 mM MgCl₂, 3 μMpeptide, 2.5 mM DTT, 50 mM NaCl and 0.15 uCi/assay [³²P]ATP. Thecontrols were reactions in the presence (negative controls) or absence(positive controls) of 50 mM EDTA. Reactions were allowed to proceed for90 min at room temperature. The reaction products were quantified usingScintillation Proximity technolgy. The reactions were quenched by theaddition of 200 ul of a solution containing 0.3 mg streptavidin SPAbeads from Amersham, 50 mM EDTA, 0.1% TX-100, 50 uM ATP, in PBS, pH7.2(phosphate buffered solution). Plates were sealed and counted in aPackard Topcount scintillation counter. IC50 values were obtained byfitting raw data to the equation y-Vmax*(1−(x/(k+x))).

The results shown in Table 7 summarise representative data: Table 7illustrates the inhibitory activity of compounds of the presentinvention against several different kinases (VEGFR2, CDK2, Tie-2, andc-fms).

TABLE 7 Kinase inhibition data of representative compounds CompoundVEGFR2 CDK2 Tie-2 c-fms Example 24 +++ ++ + + Example 29 +++ + + +Example 30 +++ +++ + + Example 32 +++ ++ + + Example 48 ++++ +++ + +Example 55 ++++ +++ + + Example 58 +++ +++ + Example 63 ++++ + Example66 ++++ + Example 71 +++ + Example 72 ++++ + Key (IC₅₀, nM) 1-10: ++++11-50: +++ 51-100: ++ >100: +

VEGF-R2 receptor kinase mediates intracellular signal transductionproduced by extracellular receptor binding of Vascular EndothelialGrowth Factor (VEGF) in the endothelial cells involved in angiogenesis.An inhibitor of VEGF-R2 receptor kinase can therefore block mitogenesisin endothelial cells, and will show selectivity (greater inhibition)compared to effects of other growth factors. An assay to measure thiseffect involves measurement of the inhibition of bromo-deoxy uridine(BrdU) incorporation (evidence of DNA synthesis) in human umbilical veinendothelial cells (HUVECs). Selectivity is demonstrated by comparison tothe inhibition of BrdU incorporation prompted by basic Fibroblast GrowthFactor (bFGF). These assays are described below.

HUVEC BrdU incorporation

Materials

HUVEC cells and EGM (Endothelial cell growth medium) were purchased fromClonetics (San Diego, Calif.). VEGF and bFGF were purchased fromGenzyme. M199 medium (Gibco BRL) with BSA (Sigma) was used for cellculture in Type I collagen coated plates (Becton Dickinson). The degreeof BrdU incorporation was measured using a commercial colorimetric ELISAassay from Boehringer Mannheim.

Method

HUVECs were plated at a density of 2500 cells per well in M199 mediumcontaining 5% FBS (Hyclone) in a Type-I Collagen coated plate. The platewas incubated at 37° C. overnight. The medium was removed by aspiration,and test compounds were added to each well in a volume of 0.1 ml perwell in serum-free M199 medium. Compound concentrations ranged from 0.15nM to 3.0 micromolar. The plate was incubated for 30 min at 37° C.Another 0.1 ml of serum-free M199 medium containing BSA and VEGF (orbFGF) was added to give a final concentration of 0.1% BSA and 20 ng/mlVEGF (0.3 ng/ml bFGF). The plate was incubated at 37° C. for 72 hrs.BrdU was added to each well after the first 48 hrs to give aconcentration of 10 micomolar. The calorimetric ELISA assay wasperformed according to manufacturer's instructions, with detection byabsorbance reading at 450 nm. Results were plotted as concentration oftest compound vs. absorbance to give an IC₅₀ value for inhibition ofBrdU incorporation.

Values of IC₅₀ inhibition for VEGF and bFGF by representative compoundsare given in Table 8.

TABLE 8 Inhibition of BrdU incorporation in HUVEC cells VEGF BFGFCompound stimulation Stimulation Example 24 ++++ + Example 29 ++++ +Example 30 ++++ ++ Example 32 ++++ ++ Example 48 ++++ +++ Example 55++ + Example 58 ++++ ++ Example 63 ++++ +++ Example 66 +++ + Example 71++++ ++++ Example 72 ++++ ++++ Key (IC₅₀, μM) 0.01-0.5: ++++ 0.6-1.0:+++ 1.1-5.0: ++ >5.0: +

UTILITY OF INVENTION

Inhibitors of VEGF-R2 kinase have utility as agents in the treatment ofa wide variety of disorders which have a proliferative componentdependent upon angiogenesis. These include, for example, cancers,arthritis, diabetic retinopathy, macular degeneration, and psoriasis.

The tumour inhibitory activity of the compounds of the present inventioncan be demonstrated in vivo, using Swiss Nu/Nu female mice in whichmouse or human tumor cell lines have been implanted subcutaneously.Typical tumor types are the murine Lewis lung tumor and the human HT-29colon carcinoma. In this assay, the compounds induce a marked reductionin the average tumour volume compared to vehicle treated controls.

The present invention demonstrates methodologies by which the process ofangiogenesis induced by abnormal release of Vascular Endothelial GrowthFactor (VEGF) may be inhibited by treatment with inhibitors of VEGF-R2receptor tyrosine kinase. Proliferative disorders and other disordersinvolving abnormal angiogenesis can therefore be treated.

When the compounds of the present invention are used in conjunction withchemotherapeutic agents or radiation therapy for cancer treatment, theyprovide a secondary means of suppressing tumor growth either whenadministered simultaneously with chemotherapeutic agents, or in analternating regimen to suppress tumor growth between chemotherapeutic orradiation treatments.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for cancerconditions, or for other indications for the compounds of the inventionas indicated above. Likewise, the specific pharmacologic responsesobserved may vary according to and depending upon the particular activecompound selected or whether there are present certain pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention. It is intended, therefore, that the invention be limited onlyby the scope of the claims which follow and that such claims beinterpreted as broadly as is reasonable.

The application of which this description and claim(s) forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, formulation, process or use claims and may include, by way ofexample and without limitation, one or more of the following claim(s).

What is claimed is:
 1. A compound of the formula (I):

wherein Y, Z, A, and D are carbon; X is N; R¹ is selected from the groupconsisting of: hydrogen, C₁₋₁₂ aliphatic, thiol, hydroxy, hydroxy-C₁₋₁₂aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic, R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc,Cyc-C₁₋₆ aliphatic, Het, Het-C1-2aliphatic, C₁₋₁₂alkoxy, Aryloxy, amino,C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphaticaminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂ alkoxycarbonyl,fluoro, bromo, iodo, cyano, sulfonamide, or nitro, where R⁹, Aryl, Cycand Het are as defined below; R² is selected from the group consistingof: hydrogen, C₁₋₁₂ aliphatic, N-hydroxyimino-C₁₋₁₂ aliphatic, C₁₋₁₂alkoxy, hydroxy-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxycarbonyl, carboxyl C₁₋₁₂aliphatic, Aryl, R⁹-Aryl-oxycarbonyl, R⁹-oxycarbonyl-Aryl, Het,aminocarbonyl, C₁₋₁₂ aliphatic-aminocarbonyl, Aryl-C₁₋₁₂aliphatic-aminocarbonyl, R⁹-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,Het-C₁₋₁₂ aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂aliphatic-aminocarbonyl, C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl,C₁₋₁₂ alkoxy-C₁₋₁₂ aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, hydroxy,C₁₋₁₂ aliphatic-sulfonyl, aminosulfonyl, and C₁₋₁₂aliphatic-aminosulfonyl, where R⁹, Aryl and Het are as defined below,where R² is not 3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl; R¹and R² are optionally joined to form a fused ring selected from thegroup as defined for Het below, and said fused ring is optionallysubstituted by a substituent selected from the group consisting of:C₁₋₁₂ aliphatic, halogen, nitro, cyano, C₁₋₁₂ alkoxy, amino, hydroxyl,(R¹⁰, R¹¹)-amino, and oxo; R³ is selected from the group consisting of:hydrogen, C₁₋₁₂ aliphatic, hydroxy, hydroxy C₁₋₁₂ aliphatic, di-C₁₋₁₂aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂ aliphaticaminosulfonyl, C₁₋₁₂ alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het,hydroxy-Het, or Het-oxy, where Aryl and Het are as defined below; R² andR³ are optionally joined to form a fused ring selected from the group asdefined for Het below, and said fused ring is optionally substituted byC₁₋₆ aliphatic or C₁₋₆ aliphatic-carbonyl; with the proviso that R¹, R²,and R³ cannot simultaneously be hydrogen; R⁴, R⁵ and R⁶ may be the sameor different and are independently selected from the group consistingof: hydrogen, C₁₋₁₂ aliphatic, thiol, C₁₋₆aliphatic-thio,di(trifluoromethyl)hydroxymethyl, carboxamide, mono-C₁₋₂aliphaticaminocarbonyl, hydroxy, hydroxy-C₁₋₁₂ aliphatic, Aryl, Aryl-C₁₋₁₂aliphatic, R⁹-Aryl-C₁₋₁₂ aliphatic, Cyc, Cyc-C₁₋₆ aliphatic, Het,Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy, Het-oxy, amino,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic aminocarbonyl, (R¹⁰,R¹¹)-amino-C₁₋₁₂aliphatic alkoxycarbonyl, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphaticaminocarbonylamino, (R¹⁰, R¹¹)-amino-C₁₋₆ aliphatic alkoxycarbonylamino,(R¹⁰,R¹¹)-amino-C₁₋₆ aliphaticsulfonyl, Het-C₁₋₆ aliphaticaminocarbonyl, Het-C₁₋₆ aliphatic aminocarbonylamino, Het-C₁₋₆alkoxycarbonylamino, Het-C₁₋₆ aliphatic carbonyl, Het-C₁₋₆alkoxycarbonyl, C₁₋₆ aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl, C₁₋₆aliphaticsulfonyl-C₁₋₆ aliphatic aminoalkyl-Het-, C₁₋₆ alkoxycarbonyl,C₁₋₆ aliphatic carbonylamino, (C₁₋₆ aliphatic carbonyl)(C₁₋₆aliphatic)amino, (R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonylamino,[(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic carbonyl][C₁₋₆ aliphatic]amino,(R¹⁰,R¹¹)-amino-C₁₋₆ aliphatic sulfonylamino, [(R¹⁰,R¹¹)-amino-C₁₋₆aliphaticsulfonyl][C₁₋₆ aliphatic]amino, halogen, cyano,diethoxyphosphorylmethyl, trifluromethyl, and trifluoromethoxy, whereR⁹, R¹⁰, R¹¹, Aryl, Cyc and Het are as defined below; R⁷ and R⁸ may bethe same or different and are independently selected from the groupconsisting of: hydrogen, halogen, C₁₋₂ alkoxy, hydroxy, and C₁₋₃aliphatic; with the proviso that R⁴, R⁵, R⁶, R⁷, and R⁸ cannotsimultaneously be hydrogen; wherein R⁷ may additionally be optionallyfused to R⁵ so as to form a fused benzo ring from the R⁵ to the R⁷positions; R⁹ is selected from the group consisting of: C₁₋₁₂ aliphatic,hydroxy, C₁₋₁₂ alkoxy and halogen; R¹⁰ and R¹¹ may be the same ordifferent and are independently selected from the group consisting of:hydrogen, C₁₋₆ aliphatic and Het; Aryl is selected from the groupconsisting of: phenyl, naphthyl, phenanthryl and anthracenyl; Cyc isselected from the group consisting of: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally hasone or more degrees of unsaturation; Het is a saturated or unsaturatedheteroatom ring system selected from the group consisting of:benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane,dithiazine, dithiazole, dithiolane, furan, imidazole, isoquinoline,morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine,oxadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine,pyrimidine, pyrrole, pyrrolidine, quinoline, tetrahydrofuran, tetrazine,thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole,thiomorpholine, thiophene, thiopyran, triazine and triazole, where anyof said heterocyclic rings may be optionally substituted by asubstituent selected from the group consisting of: C₁₋₁₂ aliphatic,hydroxy, C₁₋₁₂ alkoxy, (R¹⁰,R¹¹)-amino, (R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic,(R¹⁰,R¹¹)-amino-C₁₋₁₂ aliphatic amino, oxo and dioxo; and thepharmaceutically acceptable salts or solvates thereof in eithercrystalline or amorphous form.
 2. A compound as claimed in claim 1 inthe form of a substantially pure E geometric isomer.
 3. A compound asclaimed in claim 1 in the form of a substantially pure Z geometricisomer.
 4. A compound as claimed in claim 1 in the form of a mixture ofE geometric isomer and Z geometric isomer in any proportions of saidgeometric isomers.
 5. A compound as claimed in claim 1, wherein R¹ ishydrogen, fluoro, bromo, iodo, lower alkyl, cyano or nitro.
 6. Acompound as claimed in claim 1, wherein R² is hydrogen, lower alkyl,lower alkoxy, hydroxy lower alkyl, C₁₋₁₂ alkoxycarbonyl, Aryl, Het,aminocarbonyl, lower alkyl aminocarbonyl, halogen or hydroxy.
 7. Acompound as claimed in claim 1, wherein R¹ is joined with R² to form afused ring structure selected from the group consisting of: thiazole,imidazole, triazole and pyridine.
 8. A compound as claimed in claim 1,wherein R⁴ is hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl,carboxamide, mono-lower alkyl aminocarbonyl, substituted Aryl-loweralkyl, Het, Het-lower alkyl, lower alkoxy, Aryloxy, Het-oxy, amino,mono- or di-lower alkyl-amino lower alkyl aminocarbonyl, mono- ordi-lower alkyl-amino lower alkoxycarbonyl, mono- or di-lower alkyl-aminolower alkyl aminocarbonylamino, mono- or di-lower alkyl-amino loweralkoxycarbonylamino, lower alkyl carbonylamino, (lower alkylcarbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower alkylcarbonylamino, (mono- or di-lower alkyl-amino lower alkylcarbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower alkylsulfonylamino, (mono- or di-lower alkyl-amino lower alkylsulfonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower alkylsulfonyl, Het lower alkyl aminocarbonyl, Het lower alkylaminocarbonylamino, Het lower alkoxycarbonylamino, Het lower alkylcarbonyl, Het lower alkoxycarbonyl, lower alkyl sulfonyl lower alkylaminoalkyl, lower alkyl sulfonyl-lower alkyl-aminoalkyl-Het-, loweralkoxycarbonyl, halogen, cyano, diethoxyphosphorylmethyl, trifluromethylor trifluoromethoxy.
 9. A compound as claimed in claim 1, wherein R⁵ ishydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, carboxamide,mono-lower alkyl aminocarbonyl, substituted Aryl-lower alkyl, Het,Het-lower alkyl, lower alkoxy, Aryloxy, Het-oxy, amino, mono- ordi-lower alkyl-amino lower alkyl aminocarbonyl, mono- or di-loweralkyl-amino lower alkoxycarbonyl, mono- or di-lower alkyl-amino loweralkyl aminocarbonylamino, mono- or di-lower alkyl-amino loweralkoxycarbonylamino, lower alkyl carbonylamino, (lower alkylcarbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower alkylcarbonylamino, (mono- or di-lower alkyl-amino lower alkylcarbonyl)(lower alkyl)amino, mono- or di-lower alkyl-amino lower alkylsulfonylamino, (mono- or di-lower alkyl-amino lower alkylsulfonyl][lower alkyl)amino, mono- or di-lower alkyl-amino lower alkylsulfonyl, Het lower alkyl aminocarbonyl, Het lower alkylaminocarbonylamino, Het lower alkoxycarbonylamino, Het lower alkylcarbonyl, Het lower alkoxycarbonyl, lower alkyl sulfonyl lower alkylaminoalkyl, lower alkyl sulfonyl-lower alkyl-aminoalkyl-Het-, loweralkoxycarbonyl, halogen, cyano, diethoxyphosphorylmethyl, trifluromethylor trifluoromethoxy, onyl, Het lower alkyl aminocarbonyl, Het loweralkyl carbonyl, lower alkyl sulfonyl lower alkyl aminoalkyl, lower alkylsulfonyl-lower alkyl-aminoalkyl-Het-, halogen, cyano and trifluromethyl.Most highly preferred are hydroxymethyl, hydroxyethyl, 4-pyridylmethyl,4-morpholino, acetamido, N-methylacetamido, carboxamide,diethylaminoethylsulfonyl, 5-methyl-3-pyrazolon-1-yl and3-ethyl-piperidine-2,6-dion-3-yl.
 10. A compound as claimed in claim 1,wherein R⁶ is hydrogen.
 11. A compound as claimed in claim 1, wherein R⁷is hydrogen, halogen or methyl.
 12. A compound as claimed in claim 1,wherein R⁸ is hydrogen, halogen or methyl.
 13. A compound as claimed inclaim 1, in Z, E or Z and E form, selected from the group consisting of:3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-[N-(4-methoxyphenyl)hydrazone];3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-{N-[4-(1,3-oxazol-5-yl)phenyl]hydrazone};3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-[N-(4-methylphenyl)hydrazone];3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-(N-{4-[(E)-2-(2-pyridinyl)ethenyl]phenyl}hydrazone);6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(3-methoxyphenyl)hydrazone];5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione3-[N-(4-methylphenyl)hydrazone];3,6-Dihydro[1,2,3]triazolo[4,5-e]indole-7,8-dione8-{N-[4-(trifluoromethyl)phenyl]hydrazone};6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(3-fluorophenyl)hydrazone];6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(4-fluorophenyl)hydrazone];or6H-[1,3]Thiazolo[5,4-e]indole-7,8-dione8-[N-(4-bromophenyl)hydrazone];and pharmaceutically active salts or solvates thereof.
 14. Apharmaceutical composition comprising a compound as claimed in claim 1and one or more pharmaceutically acceptable carriers, diluents orexcipients.
 15. A pharmaceutical composition comprising a compound asclaimed in claim 13 and one or more pharmaceutically acceptablecarriers, diluents or excipients.
 16. A compound as claimed in claim 1,wherein R³ is hydrogen or lower alkyl.
 17. A method of treating asusceptible cancer by inhibition of angiogenesis in a mammal, comprisingadministering to said mammal a therapeutically effective amount of acompound as claimed in claim 1.